Carboxamides as modulators of sodium channels

ABSTRACT

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/531,313, filed Jul. 11, 2017, and U.S. Provisional Application No.62/608,283, filed Dec. 20, 2017, each of which is incorporated byreference in its entirety.

BACKGROUND

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Neuropathic pain is a form of chronic pain caused by an injury to thesensory nerves (Dieleman, J. P., et al., Incidence rates and treatmentof neuropathic pain conditions in the general population. Pain, 2008.137(3): p. 681-8). Neuropathic pain can be divided into two categories,pain caused by generalized metabolic damage to the nerve and pain causedby a discrete nerve injury. The metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy.Discrete nerve injury indications include post amputation pain,post-surgical nerve injury pain, and nerve entrapment injuries likeneuropathic back pain.

Voltage-gated sodium channels (Na_(V)'s) are involved in pain signaling.Na_(V)'s are biological mediators of electrical signaling as theymediate the rapid upstroke of the action potential of many excitablecell types (e.g. neurons, skeletal myocytes, cardiac myocytes). Theevidence for the role of these channels in normal physiology, thepathological states arising from mutations in sodium channel genes,preclinical work in animal models, and the clinical pharmacology ofknown sodium channel modulating agents all point to the central role ofNav's in pain sensation (Rush, A. M. and T. R. Cummins, PainfulResearch: Identification of a Small-Molecule Inhibitor that SelectivelyTargets Na _(V)1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5);England, S., Voltage-gated sodium channels: the search forsubtype-selective analgesics. Expert Opin. Investig. Drugs 17 (12), p.1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels andnociception: recent concepts and therapeutic opportunities. Curr. Opin.Pharmacol. 8 (1), p. 50-56 (2008)). Na_(V)'s mediate the rapid upstrokeof the action potential of many excitable cell types (e.g. neurons,skeletal myocytes, cardiac myocytes), and thus are involved in theinitiation of signaling in those cells (Hille, Bertil, Ion Channels ofExcitable Membranes, Third ed. (Sinauer Associates, Inc., Sunderland,Mass., 2001)). Because of the role Nav's play in the initiation andpropagation of neuronal signals, antagonists that reduce Na_(V) currentscan prevent or reduce neural signaling and Na_(V) channels have beenconsidered likely targets to reduce pain in conditions wherehyper-excitability is observed (Chahine, M., Chatelier, A., Babich, O.,and Krupp, J. J., Voltage-gated sodium channels in neurologicaldisorders. CNS Neurol. Disord. Drug Targets 7 (2), p. 144-58 (2008)).Several clinically useful analgesics have been identified as inhibitorsof Na_(V) channels. The local anesthetic drugs such as lidocaine blockpain by inhibiting Na_(V) channels, and other compounds, such ascarbamazepine, lamotrigine, and tricyclic antidepressants that haveproven effective at reducing pain have also been suggested to act bysodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects oftheir mechanisms of action. Eur. J. Pain 6 Suppl. A, p. 3-9 (2002);Wang, G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na⁺currents by antidepressant sertraline and paroxetine. J. Membr. Biol.222 (2), p. 79-90 (2008)).

The Nav's form a subfamily of the voltage-gated ion channel super-familyand comprises 9 isoforms, designated Na_(V)1.1-Na_(V)1.9. The tissuelocalizations of the nine isoforms vary. Na_(V)1.4 is the primary sodiumchannel of skeletal muscle, and Na_(V)1.5 is primary sodium channel ofcardiac myocytes. Na_(V)'s 1.7, 1.8 and 1.9 are primarily localized tothe peripheral nervous system, while Na_(V)'s 1.1, 1.2, 1.3, and 1.6 areneuronal channels found in both the central and peripheral nervoussystems. The functional behaviors of the nine isoforms are similar butdistinct in the specifics of their voltage-dependent and kineticbehavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G.,International Union of Pharmacology. XLVII. Nomenclature andstructure-function relationships of voltage-gated sodium channels.Pharmacol. Rev. 57 (4), p. 397 (2005)).

Upon their discovery, Na_(V)1.8 channels were identified as likelytargets for analgesia (Akopian, A. N., L. Sivilotti, and J. N. Wood, Atetrodotoxin-resistant voltage-gated sodium channel expressed by sensoryneurons. Nature, 1996. 379(6562): p. 257-62). Since then, Na_(V)1.8 hasbeen shown to be a carrier of the sodium current that maintains actionpotential firing in small DRG neurons (Blair, N. T. and B. P. Bean,Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na⁺current, and Ca²⁺ current in the action potentials of nociceptivesensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90). Na_(V)1.8 isinvolved in spontaneous firing in damaged neurons, like those that driveneuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na⁺channel Na_(V)1.8 is essential for the expression of spontaneousactivity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3):p. 921-6; Jarvis, M. F., et al., A-803467, a potent and selectiveNa_(V)1.8 sodium channel blocker, attenuates neuropathic andinflammatory pain in the rat. Proc. Natl. Acad. Sci. USA, 2007. 104(20):p. 8520-5; Joshi, S. K., et al., Involvement of the TTX-resistant sodiumchannel Na_(V)1.8 in inflammatory and neuropathic, but notpost-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82; Lai, J.,et al., Inhibition of neuropathic pain by decreased expression of thetetrodotoxin-resistant sodium channel, Na_(V)1.8. Pain, 2002. 95(1-2):p. 143-52; Dong, X. W., et al., Small interfering RNA-mediated selectiveknockdown of Na(_(V))1.8 tetrodotoxin-resistant sodium channel reversesmechanical allodynia in neuropathic rats. Neuroscience, 2007. 146(2): p.812-21; Huang, H. L., et al., Proteomic profiling of neuromas revealsalterations in protein composition and local protein synthesis inhyper-excitable nerves. Mol. Pain, 2008. 4: p. 33; Black, J. A., et al.,Multiple sodium channel isoforms and mitogen-activated protein kinasesare present in painful human neuromas. Ann. Neurol., 2008. 64(6): p.644-53; Coward, K., et al., Immunolocalization of SNS/PN3 and NaN/SNS2sodium channels in human pain states. Pain, 2000. 85(1-2): p. 41-50;Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-likeimmunoreactivity in human adult and neonate injured sensory nerves. FEBSLett., 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship ofaxonal voltage-gated sodium channel 1.8 (Na_(V)1.8) mRNA accumulation tosciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem.286(46): p. 39836-47). The small DRG neurons where Na_(V)1.8 isexpressed include the nociceptors involved in pain signaling Na_(V)1.8mediates large amplitude action potentials in small neurons of thedorsal root ganglia (Blair, N. T. and B. P. Bean, Roles of tetrodotoxin(TTX)-sensitive Na⁺ current, TTX-resistant Na⁺ current, and Ca²⁺ currentin the action potentials of nociceptive sensory neurons. J. Neurosci.,2002. 22(23): p. 10277-90). Na_(V)1.8 is necessary for rapid repetitiveaction potentials in nociceptors, and for spontaneous activity ofdamaged neurons. (Choi, J. S. and S. G. Waxman, Physiologicalinteractions between Na_(V)1.7 and Na_(V)1.8 sodium channels: a computersimulation study. J. Neurophysiol. 106(6): p. 3173-84; Renganathan, M.,T. R. Cummins, and S. G. Waxman, Contribution of Na(_(V))1.8 sodiumchannels to action potential electrogenesis in DRG neurons. J.Neurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al., Thetetrodotoxin-resistant Na⁺ channel Na_(V)1.8 is essential for theexpression of spontaneous activity in damaged sensory axons of mice. J.Physiol., 2003. 550(Pt 3): p. 921-6). In depolarized or damaged DRGneurons, Na_(V)1.8 appears to be a driver of hyper-excitablility (Rush,A. M., et al., A single sodium channel mutation produces hyper- orhypoexcitability in different types of neurons. Proc. Natl. Acad. Sci.USA, 2006. 103(21): p. 8245-50). In some animal pain models, Na_(V)1.8mRNA expression levels have been shown to increase in the DRG (Sun, W.,et al., Reduced conduction failure of the main axon of polymodalnociceptive C-fibers contributes to painful diabetic neuropathy in rats.Brain, 135(Pt 2): p. 359-75; Strickland, I. T., et al., Changes in theexpression of NaV1.7, Na_(V)1.8 and Na_(V)1.9 in a distinct populationof dorsal root ganglia innervating the rat knee joint in a model ofchronic inflammatory joint pain. Eur. J. Pain, 2008. 12(5): p. 564-72;Qiu, F., et al., Increased expression of tetrodotoxin-resistant sodiumchannels Na_(V)1.8 and Na_(V)1.9 within dorsal root ganglia in a ratmodel of bone cancer pain. Neurosci. Lett., 512(2): p. 61-6).

The primary drawback to some known Na_(V) inhibitors is their poortherapeutic window, and this is likely a consequence of their lack ofisoform selectivity. Since Na_(V)1.8 is primarily restricted to theneurons that sense pain, selective Na_(V)1.8 blockers are unlikely toinduce the adverse events common to non-selective Na_(V) blockers.Accordingly, there remains a need to develop additional Na_(V) channelmodulators, preferably those that are more potent and selective forNa_(V)1.8.

SUMMARY

In one aspect, the invention relates to a compound described herein, ora pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a pharmaceutical compositioncomprising the compound, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable carriers or vehicles.

In still another aspect, the invention relates to a method of inhibitinga voltage gated sodium channel in a subject by administering thecompound, pharmaceutically acceptable salt, or pharmaceuticalcomposition to the subject.

In yet another aspect, the invention relates to a method of treating orlessening the severity in a subject of a variety of diseases, disorders,or conditions, including, but not limited to, chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy painor abdominoplasty pain), visceral pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, pathological cough, andcardiac arrhythmia, by administering the compound, pharmaceuticallyacceptable salt, or pharmaceutical composition to the subject.

DETAILED DESCRIPTION

In one aspect, the invention relates to a compound of formula (I-A)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

X₅ is N or CR₅;

X₆ is N or CR₆;

X₇ is N or CR₇;

X₉ is N or CR₉;

X₁₀ is N or CR₁₀;

X₁₁ is N or CR₁₁;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are defined as follows:

(i) R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

(ii) R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w); and R₆ andR₇, together with the carbon atoms to which they are attached, formaring of formula:

or

(iii) R₅ and R₆, together with the carbon atoms to which they areattached, form a ring of formula:

and

R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w):

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w); or R₁₂and R₁₃, together with the carbon atoms to which they are attached, forma ring of formula:

Y₁, Y₂, Z₁, and Z₂ are each independently O or C(R₁₄)₂;

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein when R₈ is H, then at least one of X₅, X₆, and X₇ is not N orCH;

wherein when X₇ is CR₇ and R₇ is C₁-C₆ alkyl, then R_(2a) is not H;

wherein when R_(4a) is halo, then R_(2a) is not H;

wherein no more than one of X₅, X₆, and X₇ is N;

wherein no more than one of X₉, X₁₀, and X₁₁ is N; or

a compound of formula (I-B)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

X_(1a) is N or CH;

X_(2a) is N, N⁺—O⁻, or CR_(2a);

X_(3a) is N or CR_(3a);

X_(4a) is N or CR_(4a);

X₅ is N or CR₅;

X₆ is N or CR₆;

X₇ is N or CR₇;

X₉ is N or CR₉;

X₁₀ is N or CR₁₀;

X₁₁ is N or CR₁₁;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are defined as follows:

(i) R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

(ii) R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w); and R₆ andR₇, together with the carbon atoms to which they are attached, form aring of formula:

or

(iii) R₅ and R₆, together with the carbon atoms to which they areattached, form a ring of formula:

and

R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w):

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w); or R₁₂and R₁₃, together with the carbon atoms to which they are attached, forma ring of formula:

Y₁, Y₂, Z₁, and Z₂ are each independently O or C(R₁₄)₂;

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein when R₈ is H, then at least one of X₅, X₆, and X₇ is not N orCH;

wherein one or two of X_(1a), X_(2a), X_(3a), and X_(4a) is N or N⁺—O⁻;

wherein no more than one of X₅, X₆, and X₇ is N;

wherein no more than one of X₉, X₁₀, and X₁₁ is N; or

a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

X_(1b) is N or CR_(1b);

X₂b is N or CR_(2b);

X_(3b) is N or CR_(3b);

X_(4b) is N or CR_(4b);

X₅ is N or CR₅;

X₆ is N or CR₆;

X₇ is N or CR₇;

X₉ is N or CR₉;

X₁₀ is N or CR₁₀;

X₁₁ is N or CR₁₁;

each R is independently H or C₁-C₆ alkyl;

R_(1b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(2b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are defined as follows:

(i) R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

(ii) R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w); and R₆ andR₇, together with the carbon atoms to which they are attached, form aring of formula:

or

(iii) R₅ and R₆, together with the carbon atoms to which they areattached, form a ring of formula:

and

R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w):

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w); or R₁₂and R₁₃, together with the carbon atoms to which they are attached, forma ring of formula:

Y₁, Y₂, Z₁, and Z₂ are each independently O or C(R₁₄)₂;

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein when R₈ is H, then at least one of X₅, X₆, and X₇ is not N orCH;

wherein no more than two of X_(1b), X_(2b), X_(3b), and X_(4b) is N;

wherein no more than one of X₅, X₆, and X₇ is N;

wherein no more than one of X₉, X₁₀, and X₁₁ is N.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry,”Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry,” 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As used herein, the term “compounds of the invention” refers to thecompounds of formulas (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4),(I-A-5), (I-A-6), (I-A-7), (I-A-8), (I-B), (I-B-1), (I-B-2), (I-B-3),(I-B-4), (I-B-5), (I-B-6), (I-B-7), (I-B-8), (I-B-9), (I-B-10), (II),(II-A-1), (II-A-2), (II-B-1), (II-B-2), (II-B-3), (II-B-4), and(II-B-5), and all of the embodiments thereof, as described herein, andto the compounds identified in Tables 1, 1A, 1B, and 1C.

As described herein, the compounds of the invention comprise multiplevariable groups (e.g., L, R, X_(2a), R₅, etc.). As one of ordinary skillin the art will recognize, combinations of groups envisioned by thisinvention are those combinations that result in the formation of stableor chemically feasible compounds. The term “stable,” in this context,refers to compounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, the term “substituted,” refers to a group in which oneor more hydrogen radicals has been replaced with a specifiedsubstituent. Unless otherwise indicated, a substituted group can have asubstituent at any substitutable position of the group, and when morethan one position in any given structure can be substituted with morethan one substituent selected from a specified group, the substituentcan be either the same or different at every position. As one ofordinary skill in the art will recognize, substituted groups envisionedby this invention are those that result in the formation of stable orchemically feasible compounds.

As used herein, the term “halo” means F, Cl, Br or I.

As used herein, the term “alkyl” refers to a straight or branchedhydrocarbon chain radical group consisting solely of carbon and hydrogenatoms, containing no unsaturation, and having the specified number ofcarbon atoms, which is attached to the rest of the molecule by a singlebond. For example, a “C₁-C₆ alkyl” group is an alkyl group havingbetween one and six carbon atoms.

As used herein, the term “haloalkyl” refers to an alkyl group having thespecified number of carbon atoms, wherein one or more of the hydrogenatoms of the alkyl group are replaced by halo groups. For example, a“C₁-C₆ haloalkyl” group is an alkyl group having between one and sixcarbon atoms, wherein one or more of the hydrogen atoms of the alkylgroup are replaced by halo groups.

As used herein, the term “alkoxy” refers to a radical of the formula—OR_(a) where R_(a) is an alkyl group having the specified number ofcarbon atoms. For example, a “C₁-C₆ alkoxy” group is a radical of theformula —OR_(a) where R_(a) is an alkyl group having the between one andsix carbon atoms.

As used herein, the term “haloalkoxy” refers to an alkoxy group havingthe specified number of carbon atoms, wherein one or more of thehydrogen atoms of the of the alkyl group are replaced by halo groups.

As used herein, the term “cycloalkyl” refers to a stable, non-aromatic,mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbonradical consisting solely of carbon and hydrogen atoms, having thespecified number of carbon ring atoms, and which is attached to the restof the molecule by a single bond.

As used herein, the term “heteroaryl” refers to a stable, aromatic,mono- or bicyclic ring radical having the specified number of ring atomsand comprising one or more heteroatoms individually selected fromnitrogen, oxygen and sulfur.

As used herein, “*5,” “*6,” “*7,” “*12,” and “*13” in the followingstructures designate the carbon atom in formula (I-A), (I-A-1), (I-A-2),(I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-8), (I-B), (I-B-1),(I-B-2), (I-B-3), (I-B-4), (I-B-5), (I-B-6), (I-B-7), (I-B-8), (I-B-9),(I-B-10), (II), (II-A-1), (II-A-2), (II-B-1), (II-B-2), (II-B-3),(II-B-4), or (II-B-5) to which the corresponding R group is attached.For example, “*5” designates the carbon atom to which R₅ is attached.

Unless otherwise specified, the compounds of the invention, whetheridentified by chemical name or chemical structure, include allstereoisomers (e.g., enantiomers and diastereomers), double bond isomers(e.g., (Z) and (E)), conformational isomers, and tautomers, of thecompounds identified by the chemical names and chemical structuresprovided herein. In addition, single stereoisomers, double bond isomers,conformation isomers, and tautomers as well as mixtures ofstereoisomers, double bond isomers, conformation isomers, and tautomersare within the scope of the invention.

As used herein, in any chemical structure or formula, a bold or hashedstraight bond attached to a stereocenter of a compound, such as in

denotes the relative stereochemistry of the stereocenter, relative toother stereocenter(s) to which bold or hashed straight bonds areattached.

As used herein, in any chemical structure or formula, a bold or hashedwedge bond attached to a stereocenter of a compound, such as in

denotes the absolute stereochemistry of the stereocenter, as well as therelative stereochemistry of the stereocenter, relative to otherstereocenter(s) to which bold or hashed wedge bonds are attached.

As used herein, the prefix “rel-,” when used in connection with a chiralcompound, means that the compound was obtained as substantially a singleenantiomer, but that the absolute stereochemistry was not determined. Ina compound bearing the “rel-” prefix, the absolute stereochemistryindicated by each bold or hashed wedge bond in the chemical structureand each (R)- and (S)-designator in the chemical name was arbitrarilyassigned. Unless otherwise specified, the relative stereochemistryindicated by such bonds and designators in a compound bearing the “rel-”prefix reflects the relative stereochemistry of the compound.

As used herein, the term “compound,” when referring to the compounds ofthe invention, refers to a collection of molecules having identicalchemical structures, except that there may be isotopic variation amongthe constituent atoms of the molecules. The term “compound” includessuch a collection of molecules without regard to the purity of a givensample containing the collection of molecules. Thus, the term “compound”includes such a collection of molecules in pure form, in a mixture(e.g., solution, suspension, or colloid) with one or more othersubstances, or in the form of a hydrate, solvate, or co-crystal.

In the specification and claims, unless otherwise specified, any atomnot specifically designated as a particular isotope in any compound ofthe invention is meant to represent any stable isotope of the specifiedelement. In the Examples, where an atom is not specifically designatedas a particular isotope in any compound of the invention, no effort wasmade to enrich that atom in a particular isotope, and therefore a personof ordinary skill in the art would understand that such atom likely waspresent at approximately the natural abundance isotopic composition ofthe specified element.

As used herein, the term “stable,” when referring to an isotope, meansthat the isotope is not known to undergo spontaneous radioactive decay.Stable isotopes include, but are not limited to, the isotopes for whichno decay mode is identified in V. S. Shirley & C. M. Lederer, IsotopesProject, Nuclear Science Division, Lawrence Berkeley Laboratory, Tableof Nuclides (January 1980).

As used herein in the specification and claims, “H” refers to hydrogenand includes any stable isotope of hydrogen, namely ¹H and D. In theExamples, where an atom is designated as “H,” no effort was made toenrich that atom in a particular isotope of hydrogen, and therefore aperson of ordinary skill in the art would understand that such hydrogenatom likely was present at approximately the natural abundance isotopiccomposition of hydrogen.

As used herein, “¹H” refers to protium. Where an atom in a compound ofthe invention, or a pharmaceutically acceptable salt thereof, isdesignated as protium, protium is present at the specified position atat least the natural abundance concentration of protium.

As used herein, “D,” “d,” and “²H” refer to deuterium.

In some embodiments, the compounds of the invention, andpharmaceutically acceptable salts thereof, include each constituent atomat approximately the natural abundance isotopic composition of thespecified element.

In some embodiments, the compounds of the invention, andpharmaceutically acceptable salts thereof, include one or more atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the most abundant isotope of the specified element(“isotope-labelled” compounds and salts). Examples of stable isotopeswhich are commercially available and suitable for the invention includewithout limitation isotopes of hydrogen, carbon, nitrogen, oxygen, andphosphorus, for example ²H, ¹³C, ¹⁵N, ¹⁸O, ¹⁷O, and ³¹P, respectively.

The isotope-labelled compounds and salts can be used in a number ofbeneficial ways, including as medicaments. In some embodiments, theisotope-labelled compounds and salts are deuterium (²H)-labelled.Deuterium (²H)-labelled compounds and salts are therapeutically usefulwith potential therapeutic advantages over the non-²H-labelledcompounds. In general, deuterium (²H)-labelled compounds and salts canhave higher metabolic stability as compared to those that are notisotope-labelled owing to the kinetic isotope effect described below.Higher metabolic stability translates directly into an increased in vivohalf-life or lower dosages, which under most circumstances wouldrepresent a preferred embodiment of the present invention. Theisotope-labelled compounds and salts can usually be prepared by carryingout the procedures disclosed in the synthesis schemes, the examples andthe related description, replacing a non-isotope-labelled reactant by areadily available isotope-labelled reactant.

The deuterium (²H)-labelled compounds and salts can manipulate the rateof oxidative metabolism of the compound by way of the primary kineticisotope effect. The primary kinetic isotope effect is a change of therate for a chemical reaction that results from exchange of isotopicnuclei, which in turn is caused by the change in ground state energiesof the covalent bonds involved in the reaction. Exchange of a heavierisotope usually results in a lowering of the ground state energy for achemical bond and thus causes a reduction in the rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(H)/k_(D)=2-7 aretypical. For a further discussion, see S. L. Harbeson and R. D. Tung,Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011,46, 403-417, incorporated in its entirety herein by reference.

The concentration of an isotope (e.g., deuterium) incorporated at agiven position of an isotope-labelled compound of the invention, or apharmaceutically acceptable salt thereof, may be defined by the isotopicenrichment factor. The term “isotopic enrichment factor,” as usedherein, means the ratio between the abundance of an isotope at a givenposition in an isotope-labeled compound (or salt) and the naturalabundance of the isotope.

Where an atom in a compound of the invention, or a pharmaceuticallyacceptable salt thereof, is designated as deuterium, such compound (orsalt) has an isotopic enrichment factor for such atom of at least 3000(45% deuterium incorporation). In some embodiments, the isotopicenrichment factor is at least 3500 (52.5% deuterium incorporation), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It may be reasonable to assumethat many compounds with poor pharmacokinetic profiles are susceptibleto oxidative metabolism.

In one aspect, the invention relates to a compound of formula (I-A)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

X₅ is N or CR₅;

X₆ is N or CR₆;

X₇ is N or CR₇;

X₉ is N or CR₉;

X₁₀ is N or CR₁₀;

X₁₁ is N or CR₁₁;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are defined as follows:

(i) R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

(ii) R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w); and R₆ andR₇, together with the carbon atoms to which they are attached, form aring of formula:

or

(iii) R₅ and R₆, together with the carbon atoms to which they areattached, form a ring of formula:

and

R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w):

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w); or R₁₂and R₁₃, together with the carbon atoms to which they are attached, forma ring of formula:

Y₁, Y₂, Z₁, and Z₂ are each independently O or C(R₁₄)₂;

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein when R₈ is H, then at least one of X₅, X₆, and X₇ is not N orCH;

wherein when X₇ is CR₇ and R₇ is C₁-C₆ alkyl, then R_(2a) is not H;

wherein when R_(4a) is halo, then R_(2a) is not H;

wherein no more than one of X₅, X₆, and X₇ is N;

wherein no more than one of X₉, X₁₀, and X₁₁ is N.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein L is O ora single bond. In other embodiments, L is O. In other embodiments, L isa single bond.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X₅ is N.In other embodiments, X₅ is CR₅.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X₆ is N.In other embodiments, X₆ is CR₆.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X₇ is N.In other embodiments, X₇ is CR₇.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X₉ is N.In other embodiments, X₉ is CR₉.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X₁₀ is N.In other embodiments, X₁₀ is CR₁₀.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X₁₁ is N.In other embodiments, X₁₁ is CR₁₁.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein each R isindependently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R_(2a) isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R_(2a)is halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R_(2a)is H, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R_(2a) is H, halo,OH, or C₁-C₆ alkyl. In other embodiments, R_(2a) is halo. In otherembodiments, R_(2a) is C₁-C₆ alkyl. In other embodiments, R_(2a) isC₁-C₆ alkoxy. In other embodiments, R_(2a) is H, F, Cl, OH, CH₃, orOCH₃. In other embodiments, R_(2a) is H. In other embodiments, R_(2a) isF. In other embodiments, R_(2a) is Cl. In other embodiments, R_(2a) isOH. In other embodiments, R_(2a) is CH₃. In other embodiments, R_(2a) isOCH₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R_(3a) isH or halo. In other embodiments, R_(3a) is halo. In other embodiments,R_(3a) is H or F. In other embodiments, R_(3a) is H. In otherembodiments, R_(3a) is F.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R_(4a) isH or C₁-C₆ alkyl. In other embodiments, R_(4a) is C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or CH₃. In other embodiments, R_(4a) is H. Inother embodiments, R_(4a) is ¹H. In other embodiments, R_(4a) is D. Inother embodiments, R_(4a) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,or C₁-C₆ alkoxy. In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, or C₁-C₆ haloalkyl. In other embodiments, R₅ is halo. In otherembodiments, R₅ is C₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆haloalkyl. In other embodiments, R₅ is C₁-C₆ alkoxy. In otherembodiments, R₅ is H, F, CF₃, or OCH₃. In other embodiments, R₅ is H. Inother embodiments, R₅ is F. In other embodiments, R₅ is CF₃. In otherembodiments, R₅ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is H, F, Cl, CHF₂, CF₃,CF₂CF₃, OCF₃, or cyclopropyl. In other embodiments, R₆ is H. In otherembodiments, R₆ is F. In other embodiments, R₆ is Cl. In otherembodiments, R₆ is CHF₂. In other embodiments, R₆ is CF₃. In otherembodiments, R₆ is CF₂CF₃. In other embodiments, R₆ is OCF₃. In otherembodiments, R₆ is cyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₅ and R₆,together with the carbon atoms to which they are attached, forma ring offormula:

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇is H, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₇ is halo. Inother embodiments, R₇ is C₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆haloalkyl. In other embodiments, R₇ is C₁-C₆ alkoxy. In otherembodiments, R₇ is —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w), wherein W is O, n is 1, and R_(w) is phenyl, whereinsaid phenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w), whereinW is a single bond, n is 0, and R_(w) is 3-6 membered cycloalkyl,wherein said 3-6 membered cycloalkyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In other embodiments, R₇ is H,F, Cl, CH(CH₃)₂, C(CH₃)₃, CF(CH₃)₂, CF₃, OCH₃, OCH₂Ph, cyclopropyl,1-methylcylopropyl, 2-methylcyclopropyl, or 2,2-difluorocyclopropyl. Inother embodiments, R₇ is H. In other embodiments, R₇ is F. In otherembodiments, R₇ is Cl. In other embodiments, R₇ is CH(CH₃)₂. In otherembodiments, R₇ is C(CH₃)₃. In other embodiments, R₇ is CF(CH₃)₂. Inother embodiments, R₇ is CF₃. In other embodiments, R₇ is OCH₃. In otherembodiments, R₇ is OCH₂Ph. In other embodiments, R₇ is cyclopropyl. Inother embodiments, R₇ is 1-methylcylopropyl. In other embodiments, R₇ is2-methylcyclopropyl. In other embodiments, R₇ is2,2-difluorocyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₆ and R₇,together with the carbon atoms to which they are attached, form a ringof formula:

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₈ is—O—(CH₂)_(n)—R_(w). In other embodiments, R₈ is —O—(CH₂)_(n)—R_(w),wherein n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₈ is H or OCH₂Ph. In other embodiments, R₈ is H. In otherembodiments, R₈ is OCH₂Ph.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo,OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is H, halo, OH, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₉ is H, halo, OH, C₁-C₆ alkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo, OH, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is halo. In otherembodiments, R₉ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkoxy. In other embodiments, R₉ is —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₉ is H, F, Cl, OH, CH₃, OCH₃, or1-methylpyrazol-5-yl. In other embodiments, R₉ is H. In otherembodiments, R₉ is ¹H. In other embodiments, R₉ is D. In otherembodiments, R₉ is F. In other embodiments, R₉ is Cl. In otherembodiments, R₉ is OH. In other embodiments, R₉ is CH₃. In otherembodiments, R₉ is OCH₃. In other embodiments, R₉ is OC(¹H)₃. In otherembodiments, R₉ is OCD₃. In other embodiments, R₉ is1-methylpyrazol-5-yl.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₁₀ is H, halo,OH, or C₁-C₆ alkoxy. In other embodiments, R₁₀ is halo, OH, or C₁-C₆alkoxy. In other embodiments, R₁₀ is H, OH, or C₁-C₆ alkoxy. In otherembodiments, R₁₀ is H, halo, or C₁-C₆ alkoxy. In other embodiments, R₁₀is H, halo, or OH. In other embodiments, R₁₀ is halo. In otherembodiments, R₁₀ is C₁-C₆ alkoxy. In other embodiments, R₁₀ is H, F, Cl,OH, or OCH₃. In other embodiments, R₁₀ is H. In other embodiments, R₁₀is ¹H. In other embodiments, R₁₀ is D. In other embodiments, R₁₀ is F.In other embodiments, R₁₀ is Cl. In other embodiments, R₁₀ is OH. Inother embodiments, R₁₀ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₁₁ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₁₁ is H, halo,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, or C₁-C₆ alkoxy.In other embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H, F, Cl, OCH₃, or OCF₃. In other embodiments, R₁₁is H. In other embodiments, R₁₁ is ¹H. In other embodiments, R₁₁ is D.In other embodiments, R₁₁ is F. In other embodiments, R₁₁ is Cl. Inother embodiments, R₁₁ is OCH₃. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₁₂ is H.In other embodiments, R₁₂ is ¹H. In other embodiments, R₁₂ is D.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₁₃ is H.In other embodiments, R₁₃ is ¹H. In other embodiments, R₁₃ is D.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R₁₂ andR₁₃, together with the carbon atoms to which they are attached, form aring of formula:

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein Y₁ is O,and Y₂ is C(R₁₄)₂. In other embodiments, Y₁ is C(R₁₄)₂, and Y₂ is O. Inother embodiments, Y₁ is O, and Y₂ is O. In other embodiments, Y₁ isC(R₁₄)₂, and Y₂ is C(R₁₄)₂.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein Z₁ is O,and Z₂ is C(R₁₄)₂. In other embodiments, Z₁ is C(R₁₄)₂, and Z₂ is O. Inother embodiments, Z₁ is O, and Z₂ is O. In other embodiments, Z₁ isC(R₁₄)₂, and Z₂ is C(R₁₄)₂.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein each R₁₄is independently H or F. In other embodiments, each R₁₄ is H. In otherembodiments, R₁₄ is ¹H. In other embodiments, R₁₄ is D.

In other embodiments, each R₁₄ is F.

In some embodiments, the invention relates to a compound of formula(I-A), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-A-1)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H;

wherein when R₇ is C₁-C₆ alkyl, then R_(2a) is not H;

wherein when R_(4a) is halo, then R_(2a) is not H.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein L is Oor a single bond. In other embodiments, L is O. In other embodiments, Lis a single bond.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, OH, or C₁-C₆ alkyl. In other embodiments, R_(2a) is halo. Inother embodiments, R_(2a) is C₁-C₆ alkyl. In other embodiments, R_(2a)is C₁-C₆ alkoxy. In other embodiments, R_(2a) is H, F, Cl, OH, or CH₃.In other embodiments, R_(2a) is H. In other embodiments, R_(2a) is F. Inother embodiments, R_(2a) is Cl. In other embodiments, R_(2a) is OH. Inother embodiments, R_(2a) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or halo. In other embodiments, R_(3a) is halo. In otherembodiments, R_(3a) is H or F. In other embodiments, R_(3a) is H. Inother embodiments, R_(3a) is F.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H or C₁-C₆ alkyl. In other embodiments, R_(4a) is C₁-C₆ alkyl. Inother embodiments, R_(4a) is H or CH₃. In other embodiments, R_(4a) isH. In other embodiments, R_(4a) is ¹H. In other embodiments, R_(4a) isD. In other embodiments, R_(4a) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is H, F, CF₃,or OCH₃. In other embodiments, R₅ is H. In other embodiments, R₅ is F.In other embodiments, R₅ is CF₃. In other embodiments, R₅ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is H, F, Cl, CHF₂, CF₃,CF₂CF₃, OCF₃, or cyclopropyl. In other embodiments, R₆ is H. In otherembodiments, R₆ is F. In other embodiments, R₆ is Cl. In otherembodiments, R₆ is CHF₂. In other embodiments, R₆ is CF₃. In otherembodiments, R₆ is CF₂CF₃. In other embodiments, R₆ is OCF₃. In otherembodiments, R₆ is cyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w).In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₇ is halo. In other embodiments, R₇ isC₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆ haloalkyl. In otherembodiments, R₇ is C₁-C₆ alkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is O, n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 3-6 membered cycloalkyl, wherein said 3-6 memberedcycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₇ is H, F, CF₃, OCH₃, or OCH₂Ph.In other embodiments, R₇ is H. In other embodiments, R₇ is F. In otherembodiments, R₇ is CF₃. In other embodiments, R₇ is OCH₃. In otherembodiments, R₇ is OCH₂Ph.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R₈ is—O—(CH₂)_(n)—R_(w). In other embodiments, R₈ is —O—(CH₂)_(n)—R_(w),wherein n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₈ is H or OCH₂Ph. In other embodiments, R₈ is H. In otherembodiments, R₈ is OCH₂Ph.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is H, halo, OH, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₉ is H, halo, OH, C₁-C₆ alkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo, OH, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is halo. In otherembodiments, R₉ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkoxy. In other embodiments, R₉ is —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₉ is H, F, Cl, OH, CH₃, OCH₃, or1-methylpyrazol-5-yl. In other embodiments, R₉ is H. In otherembodiments, R₉ is ¹H. In other embodiments, R₉ is D. In otherembodiments, R₉ is F. In other embodiments, R₉ is Cl. In otherembodiments, R₉ is OH. In other embodiments, R₉ is CH₃. In otherembodiments, R₉ is OCH₃. In other embodiments, R₉ is OC(¹H)₃. In otherembodiments, R₉ is OCD₃. In other embodiments, R₉ is1-methylpyrazol-5-yl.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R₁₀ is halo, OH, orC₁-C₆ alkoxy. In other embodiments, R₁₀ is H, OH, or C₁-C₆ alkoxy. Inother embodiments, R₁₀ is H, halo, or C₁-C₆ alkoxy. In otherembodiments, R₁₀ is H, halo, or OH. In other embodiments, R₁₀ is halo.In other embodiments, R₁₀ is C₁-C₆ alkoxy. In other embodiments, R₁₀ isH, F, Cl, OH, or OCH₃. In other embodiments, R₁₀ is H. In otherembodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D. In otherembodiments, R₁₀ is F. In other embodiments, R₁₀ is Cl. In otherembodiments, R₁₀ is OH. In other embodiments, R₁₀ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R₁₁ isH, halo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo,or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, or C₁-C₆alkoxy. In other embodiments, R₁₁ is halo. In other embodiments, R₁₁ isC₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is F, OCH₃, or OCF₃. In other embodiments, R₁₁ is H. Inother embodiments, R₁₁ is ¹H. In other embodiments, R₁₁ is D. In otherembodiments, R₁₁ is F. In other embodiments, R₁₁ is OCH₃. In otherembodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH. In other embodiments, R₁₃ is ¹H. In other embodiments, R₁₃ is D.

In some embodiments, the invention relates to a compound of formula(I-A-1), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-A-2)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅ and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₇, and R₈ is not H;

wherein when R₇ is C₁-C₆ alkyl, then R_(2a) is not H;

wherein when R_(4a) is halo, then R_(2a) is not H.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein L is Oor a single bond. In other embodiments, L is O. In other embodiments, Lis a single bond.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, OH, or C₁-C₆ alkyl. In other embodiments, R_(2a) is halo. Inother embodiments, R_(2a) is C₁-C₆ alkyl. In other embodiments, R_(2a)is C₁-C₆ alkoxy. In other embodiments, R_(2a) is H, halo, C₁-C₆ alkyl,or C₁-C₆ alkoxy. In other embodiments, R_(2a) is H, F, CH₃, or OCH₃. Inother embodiments, R_(2a) is H. In other embodiments, R_(2a) is F. Inother embodiments, R_(2a) is CH₃. In other embodiments, R_(2a) is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or halo. In other embodiments, R_(3a) is halo. In otherembodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H or C₁-C₆ alkyl. In other embodiments, R_(4a) is C₁-C₆ alkyl. Inother embodiments, R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is H.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w).In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₇ is halo. In other embodiments, R₇ isC₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆ haloalkyl. In otherembodiments, R₇ is C₁-C₆ alkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is O, n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C haloalkyl. In otherembodiments, R₇ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 3-6 membered cycloalkyl, wherein said 3-6 memberedcycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₇ is CH(CH₃)₂, C(CH₃)₃,CF(CH₃)₂, CF₃, cyclopropyl, 1-methylcylopropyl, 2-methylcyclopropyl, or2,2-difluorocyclopropyl. In other embodiments, R₇ is CH(CH₃)₂. In otherembodiments, R₇ is C(CH₃)₃. In other embodiments, R₇ is CF(CH₃)₂. Inother embodiments, R₇ is CF₃. In other embodiments, R₇ is cyclopropyl.In other embodiments, R₇ is 1-methylcylopropyl. In other embodiments, R₇is 2-methylcyclopropyl. In other embodiments, R₇ is2,2-difluorocyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R₈ is—O—(CH₂)_(n)—R_(w). In other embodiments, R₈ is —O—(CH₂)_(n)—R_(w),wherein n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is H, halo, OH, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₉ is H, halo, OH, C₁-C₆ alkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo, OH, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is halo. In otherembodiments, R₉ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkoxy. In other embodiments, R₉ is —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or OCH₃. In other embodiments, R₉ is H. In otherembodiments, R₉ is ¹H. In other embodiments, R₉ is D. In otherembodiments, R₉ is OCH₃. In other embodiments, R₉ is OC(¹H)₃. In otherembodiments, R₉ is OCD₃.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R₁₀ is halo, OH, orC₁-C₆ alkoxy. In other embodiments, R₁₀ is H, OH, or C₁-C₆ alkoxy. Inother embodiments, R₁₀ is H, halo, or C₁-C₆ alkoxy. In otherembodiments, R₁₀ is H, halo, or OH. In other embodiments, R₁₀ is halo.In other embodiments, R₁₀ is C₁-C₆ alkoxy. In other embodiments, R₁₀ isH or halo. In other embodiments, R₁₀ is H, F or Cl. In otherembodiments, R₁₀ is H. In other embodiments, R₁₀ is ¹H. In otherembodiments, R₁₀ is D. In other embodiments, R₁₀ is F. In otherembodiments, R₁₀ is Cl.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R₁₁ isH, halo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo,or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, or C₁-C₆alkoxy. In other embodiments, R₁₁ is halo. In other embodiments, R₁₁ isC₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is halo or C₁-C₆ haloalkoxy. In other embodiments, R₁₁is F or OCF₃. In other embodiments, R₁₁ is H. In other embodiments, R₁₁is ¹H. In other embodiments, R₁₁ is D. In other embodiments, R₁₁ is F.In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-A-2), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-A-2), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-A-3)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₆ and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₆, R₇, and R₈ is not H;

wherein when R₇ is C₁-C₆ alkyl, then R_(2a) is not H;

wherein when R_(4a) is halo, then R_(2a) is not H.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, OH, or C₁-C₆ alkyl. In other embodiments, R_(2a) is halo. Inother embodiments, R_(2a) is C₁-C₆ alkyl. In other embodiments, R_(2a)is C₁-C₆ alkoxy. In other embodiments, R_(2a) is H or halo. In otherembodiments, R_(2a) is H or F. In other embodiments, R_(2a) is H. Inother embodiments, R_(2a) is F.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or halo. In other embodiments, R_(3a) is halo. In otherembodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H or C₁-C₆ alkyl. In other embodiments, R_(4a) is C₁-C₆ alkyl. Inother embodiments, R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is H.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w).In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₇ is halo. In other embodiments, R₇ isC₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆ haloalkyl. In otherembodiments, R₇ is C₁-C₆ alkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is O, n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 3-6 membered cycloalkyl, wherein said 3-6 memberedcycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₇ is CF₃.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R₈ is—O—(CH₂)_(n)—R_(w). In other embodiments, R₈ is —O—(CH₂)_(n)—R_(w),wherein n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is H, halo, OH, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₉ is H, halo, OH, C₁-C₆ alkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo, OH, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is halo. In otherembodiments, R₉ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkoxy. In other embodiments, R₉ is —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₉ is H. In other embodiments, R₉is ¹H. In other embodiments, R₉ is D. In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R₁₀ is halo, OH, orC₁-C₆ alkoxy. In other embodiments, R₁₀ is H, OH, or C₁-C₆ alkoxy. Inother embodiments, R₁₀ is H, halo, or C₁-C₆ alkoxy. In otherembodiments, R₁₀ is H, halo, or OH. In other embodiments, R₁₀ is halo.In other embodiments, R₁₀ is C₁-C₆ alkoxy. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R₁₁ isH, halo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo,or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, or C₁-C₆alkoxy. In other embodiments, R₁₁ is halo. In other embodiments, R₁₁ isC₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₀ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-A-3), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-A-3), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-A-4)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅ and R₆ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, and R₈ is not H;

wherein when R_(4a) is halo, then R_(2a) is not H.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein L is Oor a single bond. In other embodiments, L is O. In other embodiments, Lis a single bond.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, OH, or C₁-C₆ alkyl. In other embodiments, R_(2a) is halo. Inother embodiments, R_(2a) is C₁-C₆ alkyl. In other embodiments, R_(2a)is C₁-C₆ alkoxy. In other embodiments, R_(2a) is F.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or halo. In other embodiments, R_(3a) is halo. In otherembodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H or C₁-C₆ alkyl. In other embodiments, R_(4a) is C₁-C₆ alkyl. Inother embodiments, R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is H, halo, orC₁-C₆ alkoxy. In other embodiments, R₅ is H, F, or OCH₃. In otherembodiments, R₅ is H. In other embodiments, R₅ is F. In otherembodiments, R₅ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, CF₃, orcyclopropyl. In other embodiments, R₆ is H. In other embodiments, R₆ isCF₃. In other embodiments, R₆ is cyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R₈ is—O—(CH₂)_(n)—R_(w). In other embodiments, R₈ is —O—(CH₂)_(n)—R_(w),wherein n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is H, halo, OH, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₉ is H, halo, OH, C₁-C₆ alkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo, OH, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is halo. In otherembodiments, R₉ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkoxy. In other embodiments, R₉ is —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or OCH₃. In other embodiments, R₉ is H. In otherembodiments, R₉ is ¹H. In other embodiments, R₉ is D. In otherembodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R₁₀ is halo, OH, orC₁-C₆ alkoxy. In other embodiments, R₁₀ is H, OH, or C₁-C₆ alkoxy. Inother embodiments, R₁₀ is H, halo, or C₁-C₆ alkoxy. In otherembodiments, R₁₀ is H, halo, or OH. In other embodiments, R₁₀ is halo.In other embodiments, R₁₀ is C₁-C₆ alkoxy. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R₁₁ isH, halo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo,or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, or C₁-C₆alkoxy. In other embodiments, R₁₁ is halo. In other embodiments, R₁₁ isC₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is halo or C₁-C₆ haloalkoxy. In other embodiments, R₁₁is F or OCF₃. In other embodiments, R₁₁ is H. In other embodiments, R₁₁is ¹H. In other embodiments, R₁₁ is D. In other embodiments, R₁₁ is F.In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-A-4), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-A-4), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-A-5)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉ and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H;

wherein when R₇ is C₁-C₆ alkyl, then R_(2a) is not H;

wherein when R_(4a) is halo, then R_(2a) is not H.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, OH, or C₁-C₆ alkyl. In other embodiments, R_(2a) is halo. Inother embodiments, R_(2a) is C₁-C₆ alkyl. In other embodiments, R_(2a)is C₁-C₆ alkoxy. In other embodiments, R_(2a) is F.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or halo. In other embodiments, R_(3a) is halo. In otherembodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H or C₁-C₆ alkyl. In other embodiments, R_(4a) is C₁-C₆ alkyl. Inother embodiments, R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is H or halo.In other embodiments, R₅ is H or F. In other embodiments, R₅ is H. Inother embodiments, R₅ is F.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is halo, C₁-C₆ alkyl, orC₁-C₆ haloalkyl. In other embodiments, R₆ is Cl or CF₃. In otherembodiments, R₆ is Cl. In other embodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w).In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₇ is halo. In other embodiments, R₇ isC₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆ haloalkyl. In otherembodiments, R₇ is C₁-C₆ alkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is O, n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 3-6 membered cycloalkyl, wherein said 3-6 memberedcycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇is H or halo. In other embodiments, R₇ is H or Cl. In other embodiments,R₇ is H. In other embodiments, R₇ is Cl.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R₈ is—O—(CH₂)_(n)—R_(w). In other embodiments, R₈ is —O—(CH₂)_(n)—R_(w),wherein n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is H, halo, OH, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₉ is H, halo, OH, C₁-C₆ alkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo, OH, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is halo. In otherembodiments, R₉ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkoxy. In other embodiments, R₉ is —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or OCH₃. In other embodiments, R₉ is H. In otherembodiments, R₉ is ¹H. In other embodiments, R₉ is D. In otherembodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R₁₁ isH, halo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo,or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, or C₁-C₆alkoxy. In other embodiments, R₁₁ is halo. In other embodiments, R₁₁ isC₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H, Cl, OCH₃, or OCF₃. In other embodiments, R₁₁ isH. In other embodiments, R₁₁ is ¹H. In other embodiments, R₁₁ is D. Inother embodiments, R₁₁ is Cl. In other embodiments, R₁₁ is OCH₃. Inother embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-A-5), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-A-5), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-A-6)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H;

wherein when R₇ is C₁-C₆ alkyl, then R_(2a) is not H;

wherein when R_(4a) is halo, then R_(2a) is not H.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, OH, or C₁-C₆ alkyl. In other embodiments, R_(2a) is halo. Inother embodiments, R_(2a) is C₁-C₆ alkyl. In other embodiments, R_(2a)is C₁-C₆ alkoxy. In other embodiments, R_(2a) is F.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or halo. In other embodiments, R_(3a) is halo. In otherembodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H or C₁-C₆ alkyl. In other embodiments, R_(4a) is C₁-C₆ alkyl. Inother embodiments, R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is F.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w).In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₇ is halo. In other embodiments, R₇ isC₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆ haloalkyl. In otherembodiments, R₇ is C₁-C₆ alkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is O, n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 3-6 membered cycloalkyl, wherein said 3-6 memberedcycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R₈ is—O—(CH₂)_(n)—R_(w). In other embodiments, R₈ is —O—(CH₂)_(n)—R_(w),wherein n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is H, halo, OH, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₉ is H, halo, OH, C₁-C₆ alkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo, OH, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is halo. In otherembodiments, R₉ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkoxy. In other embodiments, R₉ is —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₉ is H. In other embodiments, R₉is ¹H. In other embodiments, R₉ is D.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R₁₀ is halo, OH, orC₁-C₆ alkoxy. In other embodiments, R₁₀ is H, OH, or C₁-C₆ alkoxy. Inother embodiments, R₁₀ is H, halo, or C₁-C₆ alkoxy. In otherembodiments, R₁₀ is H, halo, or OH. In other embodiments, R₁₀ is halo.In other embodiments, R₁₀ is C₁-C₆ alkoxy. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein R₁₁ isH, halo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo,or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, or C₁-C₆alkoxy. In other embodiments, R₁₁ is halo. In other embodiments, R₁₁ isC₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D.

In some embodiments, the invention relates to a compound of formula(I-A-6), or a pharmaceutically acceptable salt thereof, wherein each R₁₄is H.

In some embodiments, the invention relates to a compound of formula(I-A-6), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-A-7)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein when R_(4a) is halo, then R_(2a) is not H.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, OH, or C₁-C₆ alkyl. In other embodiments, R_(2a) is halo. Inother embodiments, R_(2a) is C₁-C₆ alkyl. In other embodiments, R_(2a)is C₁-C₆ alkoxy. In other embodiments, R_(2a) is F.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or halo. In other embodiments, R_(3a) is halo. In otherembodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H or C₁-C₆ alkyl. In other embodiments, R_(4a) is C₁-C₆ alkyl. Inother embodiments, R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is H.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R₈ is—O—(CH₂)_(n)—R_(w). In other embodiments, R₈ is —O—(CH₂)_(n)—R_(w),wherein n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is H, halo, OH, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₉ is H, halo, OH, C₁-C₆ alkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo, OH, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is halo. In otherembodiments, R₉ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkoxy. In other embodiments, R₉ is —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₉ is H. In other embodiments, R₉is ¹H. In other embodiments, R₉ is D. In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R₁₀ is halo, OH, orC₁-C₆ alkoxy. In other embodiments, R₁₀ is H, OH, or C₁-C₆ alkoxy. Inother embodiments, R₁₀ is H, halo, or C₁-C₆ alkoxy. In otherembodiments, R₁₀ is H, halo, or OH. In other embodiments, R₁₀ is halo.In other embodiments, R₁₀ is C₁-C₆ alkoxy. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R₁₁ isH, halo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo,or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, or C₁-C₆alkoxy. In other embodiments, R₁₁ is halo. In other embodiments, R₁₁ isC₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₀ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-A-7), or a pharmaceutically acceptable salt thereof, wherein each R₁₄is F.

In some embodiments, the invention relates to a compound of formula(I-A-7), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-A-8)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein when R₇ is C₁-C₆ alkyl, then R_(2a) is not H;

wherein when R_(4a) is halo, then R_(2a) is not H.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments,R_(2a) is H, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R_(2a) isH, halo, OH, or C₁-C₆ alkyl. In other embodiments, R_(2a) is halo. Inother embodiments, R_(2a) is C₁-C₆ alkyl. In other embodiments, R_(2a)is C₁-C₆ alkoxy. In other embodiments, R_(2a) is F.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or halo. In other embodiments, R_(3a) is halo. In otherembodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H or C₁-C₆ alkyl. In other embodiments, R_(4a) is C₁-C₆ alkyl. Inother embodiments, R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w).In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₇ is halo. In other embodiments, R₇ isC₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆ haloalkyl. In otherembodiments, R₇ is C₁-C₆ alkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is O, n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 3-6 membered cycloalkyl, wherein said 3-6 memberedcycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R₈ is—O—(CH₂)_(n)—R_(w). In other embodiments, R₈ is —O—(CH₂)_(n)—R_(w),wherein n is 1, and R_(w) is phenyl, wherein said phenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is H, halo, OH, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₉ is H, halo, OH, C₁-C₆ alkyl, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₉ is H, halo, OH, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is halo. In otherembodiments, R₉ is C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkoxy. In other embodiments, R₉ is —W—(CH₂)_(n)—R_(w). In otherembodiments, R₉ is —W—(CH₂)_(n)—R_(w), wherein W is a single bond, n is0, and R_(w) is 5-6 membered heteroaryl, wherein said 5-6 memberedheteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl. In other embodiments, R₉ is H. In other embodiments, R₉is ¹H. In other embodiments, R₉ is D.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH, halo, OH, or C₁-C₆ alkoxy. In other embodiments, R₁₀ is halo, OH, orC₁-C₆ alkoxy. In other embodiments, R₁₀ is H, OH, or C₁-C₆ alkoxy. Inother embodiments, R₁₀ is H, halo, or C₁-C₆ alkoxy. In otherembodiments, R₁₀ is H, halo, or OH. In other embodiments, R₁₀ is halo.In other embodiments, R₁₀ is C₁-C₆ alkoxy. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R₁₁ isH, halo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo,or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, or C₁-C₆alkoxy. In other embodiments, R₁₁ is halo. In other embodiments, R₁₁ isC₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-A-8), or a pharmaceutically acceptable salt thereof, wherein each R₁₄is independently H or F.

In some embodiments, the invention relates to a compound of formula(I-A-8), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula (I-B)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

X_(1a) is N or CH;

X_(2a) is N, N⁺—O⁻, or CR_(2a);

X_(3a) is N or CR_(3a);

X_(4a) is N or CR_(4a);

X₅ is N or CR₅;

X₆ is N or CR₆;

X₇ is N or CR₇;

X₉ is N or CR₉;

X₁₀ is N or CR₁₀;

X₁₁ is N or CR₁₁;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are defined as follows:

(i) R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

(ii) R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w); and R₆ andR₇, together with the carbon atoms to which they are attached, form aring of formula:

or

(iii) R₅ and R₆, together with the carbon atoms to which they areattached, form a ring of formula:

and

R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w):

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)-12_(w); orR₁₂ and R₁₃, together with the carbon atoms to which they are attached,form a ring of formula:

Y₁, Y₂, Z₁, and Z₂ are each independently O or C(R₁₄)₂;

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein when R₈ is H, then at least one of X₅, X₆, and X₇ is not N orCH;

wherein one or two of X_(1a), X_(2a), X_(3a), and X_(4a) is N or N⁺—O⁻;

wherein no more than one of X₅, X₆, and X₇ is N;

wherein no more than one of X₉, X₁₀, and X₁₁ is N.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X_(1a) isN. In other embodiments, X_(1a) is CH.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X_(2a) isN or N⁺—O⁻. In other embodiments, X_(2a) is N. In other embodiments,X_(2a) is N⁺—O⁻. In other embodiments, X_(2a) is CR_(2a).

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X_(3a) isN. In other embodiments, X_(3a) is CR_(3a).

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X_(4a) isN. In other embodiments, X_(4a) is CR_(4a).

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X₅ is N.In other embodiments, X₅ is CR₅.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X₆ is N.In other embodiments, X₆ is CR₆.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X₇ is N.In other embodiments, X₇ is CR₇.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X₉ is N.In other embodiments, X₉ is CR₉.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X₁₀ is N.In other embodiments, X₁₀ is CR₁₀.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X₁₁ is N.In other embodiments, X₁₁ is CR₁₁.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein each R isindependently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R_(2a) isH or halo. In other embodiments, R_(2a) is halo. In other embodiments,R_(2a) is H or F. In other embodiments, R_(2a) is H. In otherembodiments, R_(2a) is F.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R_(3a) isH or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. In otherembodiments, R_(3a) is H or CH₃. In other embodiments, R_(3a) is H. Inother embodiments, R_(3a) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R_(4a) isH, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo or C₁-C₆alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H, F, Cl, or CH₃. In other embodiments, R_(4a) is H. In otherembodiments, R_(4a) is F. In other embodiments, R_(4a) is Cl. In otherembodiments, R_(4a) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ alkylamino. In other embodiments, R₅ is halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆alkylamino. In other embodiments, R₅ is H, F, Cl, NHCH₃, CF₃, OCH₃, orOCH₂CH₃. In other embodiments, R₅ is H. In other embodiments, R₅ is F.In other embodiments, R₅ is Cl. In other embodiments, R₅ is NHCH₃. Inother embodiments, R₅ is CF₃. In other embodiments, R₅ is OCH₃. In otherembodiments, R₅ is OCH₂CH₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is H, F, Cl, CH₃, CHF₂,CF₃, CF₂CF₃, OCHF₂, OCF₃, or cyclopropyl. In other embodiments, R₆ is H.In other embodiments, R₆ is F. In other embodiments, R₆ is Cl. In otherembodiments, R₆ is CH₃. In other embodiments, R₆ is C(¹H)₃. In otherembodiments, R₆ is CD₃. In other embodiments, R₆ is CHF₂. In otherembodiments, R₆ is CF₃. In other embodiments, R₆ is CF₂CF₃. In otherembodiments, R₆ is OCHF₂. In other embodiments, R₆ is OCF₃. In otherembodiments, R₆ is cyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₅ and R₆,together with the carbon atoms to which they are attached, form a ringof formula:

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is halo. In otherembodiments, R₇ is C₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆haloalkyl. In other embodiments, R₇ is C₁-C₆ alkoxy. In otherembodiments, R₇ is C₁-C₆ haloalkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is H, Cl, C(CH₃)₃, CF(CH₃)₂, CF₃, OCHF₂, OCF₃,cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl,2,2-difluorocyclopropyl, or 1-trifluoromethylcyclopropyl. In otherembodiments, R₇ is H. In other embodiments, R₇ is Cl. In otherembodiments, R₇ is C(CH₃)₃. In other embodiments, R₇ is CF(CH₃)₂. Inother embodiments, R₇ is CF₃. In other embodiments, R₇ is OCHF₂. Inother embodiments, R₇ is OCF₃. In other embodiments, R₇ is cyclopropyl.In other embodiments, R₇ is 1-methylcyclopropyl. In other embodiments,R₇ is 2-methylcyclopropyl. In other embodiments, R₇ is2,2-difluorocyclopropyl. In other embodiments, R₇ is1-trifluoromethylcyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₆ and R₇,together with the carbon atoms to which they are attached, form a ringof formula:

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H, F, Cl, OH, CH₃, OCH₃, OCHF₂, or OCF₃. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D. In other embodiments, R₉ is F. In otherembodiments, R₉ is Cl. In other embodiments, R₉ is OH. In otherembodiments, R₉ is CH₃. In other embodiments, R₉ is C(¹H)₃. In otherembodiments, R₉ is CD₃. In other embodiments, R₉ is OCH₃. In otherembodiments, R₉ is OC(¹H)₃. In other embodiments, R₉ is OCD₃. In otherembodiments, R₉ is OCHF₂. In other embodiments, R₉ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH, F, or Cl. In other embodiments, R₁₀ is H. In other embodiments, R₁₀is ¹H. In other embodiments, R₁₀ is D. In other embodiments, R₁₀ is F.In other embodiments, R₁₀ is Cl.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is F, OCH₃, OCHF₂, or OCF₃. In other embodiments, R₁₁is H. In other embodiments, R₁₁ is ¹H. In other embodiments, R₁₁ is D.In other embodiments, R₁₁ is F. In other embodiments, R₁₁ is OCH₃. Inother embodiments, R₁₁ is OCHF₂. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₁₂ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₁₂ is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R₁₃ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₁₃ is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein Y₁ is O,and Y₂ is C(R₁₄)₂. In other embodiments, Y₁ is C(R₁₄)₂, and Y₂ is O. Inother embodiments, Y₁ is O, and Y₂ is O. In other embodiments, Y₁ isC(R₁₄)₂, and Y₂ is C(R₁₄)₂.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein Z₁ is O,and Z₂ is C(R₁₄)₂. In other embodiments, Z₁ is C(R₁₄)₂, and Z₂ is O. Inother embodiments, Z₁ is O, and Z₂ is O. In other embodiments, Z₁ isC(R₁₄)₂, and Z₂ is C(R₁₄)₂.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein each R₁₄is independently H or F. In other embodiments, each R₁₄ is H. In otherembodiments, each R₁₄ is F.

In some embodiments, the invention relates to a compound of formula(I-B), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-1)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

X_(2a) is N or N⁺—O⁻;

each R is independently H or C₁-C₆ alkyl;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X_(2a)is N. In other embodiments, X_(2a) is N⁺—O⁻.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. Inother embodiments, R_(3a) is H or CH₃. In other embodiments, R_(3a) isH. In other embodiments, R_(3a) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo orC₁-C₆ alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H, F, Cl, or CH₃. In other embodiments, R_(4a) is H. In otherembodiments, R_(4a) is F. In other embodiments, R_(4a) is Cl. In otherembodiments, R_(4a) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino.In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In other embodiments, R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo. In other embodiments, R₅ is C₁-C₆ alkyl. Inother embodiments, R₅ is C₁-C₆ haloalkyl. In other embodiments, R₅ isC₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is H, F, Cl, NHCH₃, CF₃, or OCH₃.In other embodiments, R₅ is H. In other embodiments, R₅ is F. In otherembodiments, R₅ is Cl. In other embodiments, R₅ is NHCH₃. In otherembodiments, R₅ is CF₃. In other embodiments, R₅ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is H, F, Cl, CH₃, CHF₂,CF₃, CF₂CF₃, OCHF₂, OCF₃, or cyclopropyl. In other embodiments, R₆ is H.In other embodiments, R₆ is F. In other embodiments, R₆ is Cl. In otherembodiments, R₆ is CH₃. In other embodiments, R₆ is C(¹H)₃. In otherembodiments, R₆ is CD₃. In other embodiments, R₆ is CHF₂. In otherembodiments, R₆ is CF₃. In other embodiments, R₆ is CF₂CF₃. In otherembodiments, R₆ is OCHF₂. In other embodiments, R₆ is OCF₃. In otherembodiments, R₆ is cyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is halo. In otherembodiments, R₇ is C₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆haloalkyl. In other embodiments, R₇ is C₁-C₆ alkoxy. In otherembodiments, R₇ is C₁-C₆ haloalkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is halo, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, Cl, CF₃, OCHF₂, OCF₃,or cyclopropyl. In other embodiments, R₇ is H. In other embodiments, R₇is Cl. In other embodiments, R₇ is CF₃. In other embodiments, R₇ isOCHF₂. In other embodiments, R₇ is OCF₃. In other embodiments, R₇ iscyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H, F, Cl, OH, CH₃, OCH₃, OCHF₂, or OCF₃. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D. In other embodiments, R₉ is F. In otherembodiments, R₉ is Cl. In other embodiments, R₉ is OH. In otherembodiments, R₉ is CH₃. In other embodiments, R₉ is C(¹H)₃. In otherembodiments, R₉ is CD₃. In other embodiments, R₉ is OCH₃. In otherembodiments, R₉ is OC(¹H)₃. In other embodiments, R₉ is OCD₃. In otherembodiments, R₉ is OCHF₂. In other embodiments, R₉ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH, F, or Cl. In other embodiments, R₁₀ is H. In other embodiments, R₁₀is ¹H. In other embodiments, R₁₀ is D. In other embodiments, R₁₀ is F.In other embodiments, R₁₀ is Cl.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is F, OCH₃, OCHF₂, or OCF₃. In other embodiments, R₁₁is H. In other embodiments, R₁₁ is ¹H. In other embodiments, R₁₁ is D.In other embodiments, R₁₁ is F. In other embodiments, R₁₁ is OCH₃. Inother embodiments, R₁₁ is OCHF₂. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-1), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-2)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅ and R₆ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w); or

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. Inother embodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo orC₁-C₆ alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H or CH₃. In other embodiments, R_(4a) is H. In otherembodiments, R_(4a) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino.In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In other embodiments, R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo. In other embodiments, R₅ is C₁-C₆ alkyl. Inother embodiments, R₅ is C₁-C₆ haloalkyl. In other embodiments, R₅ isC₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆ alkylamino. In otherembodiments, R₅ is halo or C₁-C₆ alkoxy. In other embodiments, R₅ is F,OCH₃, or OCH₂CH₃. In other embodiments, R₅ is F. In other embodiments,R₅ is OCH₃. In other embodiments, R₅ is OCH₂CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is H or C₁-C₆ haloalkyl.In other embodiments, R₆ is H or CF₃. In other embodiments, R₆ is H. Inother embodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H or C₁-C₆ alkoxy. In other embodiments, R₉ isH or OCH₃. In other embodiments, R₉ is H. In other embodiments, R₉ is¹H. In other embodiments, R₉ is D. In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-2), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-2), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-3)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅ and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. Inother embodiments, R_(3a) is H or CH₃. In other embodiments, R_(3a) isH. In other embodiments, R_(3a) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo orC₁-C₆ alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino.In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In other embodiments, R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo. In other embodiments, R₅ is C₁-C₆ alkyl. Inother embodiments, R₅ is C₁-C₆ haloalkyl. In other embodiments, R₅ isC₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆ alkylamino. In otherembodiments, R₅ is H.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is halo. In otherembodiments, R₇ is C₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆haloalkyl. In other embodiments, R₇ is C₁-C₆ alkoxy. In otherembodiments, R₇ is C₁-C₆ haloalkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R, In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w), whereinW is a single bond, n is 0, and R_(w) is 3-6 membered cycloalkyl,wherein said 3-6 membered cycloalkyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In other embodiments, R₇ isC₁-C₆ alkyl, C₁-C₆ haloalkyl, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is C(CH₃)₃, CF(CH₃)₂, CF₃, cyclopropyl,1-methylcyclopropyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, or1-trifluoromethylcyclopropyl. In other embodiments, R₇ is C(CH₃)₃. Inother embodiments, R₇ is CF(CH₃)₂. In other embodiments, R₇ is CF₃. Inother embodiments, R₇ is cyclopropyl. In other embodiments, R₇ is1-methylcyclopropyl. In other embodiments, R₇ is 2-methylcyclopropyl. Inother embodiments, R₇ is 2,2-difluorocyclopropyl. In other embodiments,R₇ is 1-trifluoromethylcyclopropyl.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D. In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-3), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-3), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-4)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R_(ea)is H.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo orC₁-C₆ alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino.In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In other embodiments, R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo. In other embodiments, R₅ is C₁-C₆ alkyl. Inother embodiments, R₅ is C₁-C₆ haloalkyl. In other embodiments, R₅ isC₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆ alkylamino. In otherembodiments, R₅ is F.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is halo. In otherembodiments, R₇ is C₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆haloalkyl. In other embodiments, R₇ is C₁-C₆ alkoxy. In otherembodiments, R₇ is C₁-C₆ haloalkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D. In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is OCF₃. In other embodiments, R₁₁ is H. In otherembodiments, R₁₁ is ¹H. In other embodiments, R₁₁ is D.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-4), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-4), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-5)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, or C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, or C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is H.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. Inother embodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino.In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In other embodiments, R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo. In other embodiments, R₅ is C₁-C₆ alkyl. Inother embodiments, R₅ is C₁-C₆ haloalkyl. In other embodiments, R₅ isC₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆ alkylamino. In otherembodiments, R₅ is F.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is halo. In otherembodiments, R₇ is C₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆haloalkyl. In other embodiments, R₇ is C₁-C₆ alkoxy. In otherembodiments, R₇ is C₁-C₆ haloalkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D. In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-5), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-5), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-6)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. Inother embodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo orC₁-C₆ alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino.In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In other embodiments, R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo. In other embodiments, R₅ is C₁-C₆ alkyl. Inother embodiments, R₅ is C₁-C₆ haloalkyl. In other embodiments, R₅ isC₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆ alkylamino. In otherembodiments, R₅ is H.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D. In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-6), or a pharmaceutically acceptable salt thereof, wherein each R₁₄is F.

In some embodiments, the invention relates to a compound of formula(I-B-6), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-7)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(ea) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅ and R₆ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R_(ea)is F.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. Inother embodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo orC₁-C₆ alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino.In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In other embodiments, R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo. In other embodiments, R₅ is C₁-C₆ alkyl. Inother embodiments, R₅ is C₁-C₆ haloalkyl. In other embodiments, R₅ isC₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆ alkylamino. In otherembodiments, R₅ is F.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is H.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D. In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-7), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-7), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-8)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R_(2a)is F.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. Inother embodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo orC₁-C₆ alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino.In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In otherembodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In other embodiments, R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo. In other embodiments, R₅ is C₁-C₆ alkyl. Inother embodiments, R₅ is C₁-C₆ haloalkyl. In other embodiments, R₅ isC₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆ alkylamino. In otherembodiments, R₅ is F.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is halo. In otherembodiments, R₇ is C₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆haloalkyl. In other embodiments, R₇ is C₁-C₆ alkoxy. In otherembodiments, R₇ is C₁-C₆ haloalkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D. In other embodiments, R₉ is OCH₃. In otherembodiments, R₉ is OC(¹H)₃. In other embodiments, R₉ is OCD₃.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-8), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-8), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-9)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)-12_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. Inother embodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo orC₁-C₆ alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H,halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is halo. In otherembodiments, R₇ is C₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆haloalkyl. In other embodiments, R₇ is C₁-C₆ alkoxy. In otherembodiments, R₇ is C₁-C₆ haloalkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is Hor halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ isH. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-9), or a pharmaceutically acceptable salt thereof, wherein each R₁₄is independently H or F.

In some embodiments, the invention relates to a compound of formula(I-B-9), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(I-B-10)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(3a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R_(3a)is H or C₁-C₆ alkyl. In other embodiments, R_(3a) is C₁-C₆ alkyl. Inother embodiments, R_(3a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R_(4a)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(4a) is halo orC₁-C₆ alkyl. In other embodiments, R_(4a) is H or C₁-C₆ alkyl. In otherembodiments, R_(4a) is H or halo. In other embodiments, R_(4a) is halo.In other embodiments, R_(4a) is C₁-C₆ alkyl. In other embodiments,R_(4a) is H.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆alkylamino. In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ alkylamino.In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ alkylamino. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ alkylamino. In other embodiments, R₅ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkylamino. In other embodiments,R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo. In other embodiments, R₅ is C₁-C₆ alkyl. Inother embodiments, R₅ is C₁-C₆ haloalkyl. In other embodiments, R₅ isC₁-C₆ alkoxy. In other embodiments, R₅ is C₁-C₆ alkylamino. In otherembodiments, R₅ is F.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R₆ isH, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo. In otherembodiments, R₆ is C₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆haloalkyl. In other embodiments, R₆ is C₁-C₆ alkoxy. In otherembodiments, R₆ is C₁-C₆ haloalkoxy. In other embodiments, R₆ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₆ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is unsubstituted 3-6membered cycloalkyl. In other embodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R₇ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w).In other embodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments,R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —W—(CH₂)_(n)—R_(w). Inother embodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is halo. In otherembodiments, R₇ is C₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆haloalkyl. In other embodiments, R₇ is C₁-C₆ alkoxy. In otherembodiments, R₇ is C₁-C₆ haloalkoxy. In other embodiments, R₇ is—W—(CH₂)_(n)—R_(w). In other embodiments, R₇ is —W—(CH₂)_(n)—R_(w),wherein W is a single bond, n is 0, and R_(w) is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl. In otherembodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R₈ isH.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R₉ isH, halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is halo, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H,halo, OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ isH, halo, OH, C₁-C₆ alkyl, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉is halo. In other embodiments, R₉ is C₁-C₆ alkyl. In other embodiments,R₉ is C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H. In other embodiments, R₉ is ¹H. In otherembodiments, R₉ is D. In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH or halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀is H. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(I-B-10), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(I-B-10), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

X_(1b) is N or CR_(1b);

X_(2b) is N or CR_(2b);

X_(3b) is N or CR_(3b);

X_(4b) is N or CR_(4b);

X₅ is N or CR₅;

X₆ is N or CR₆;

X₇ is N or CR₇;

X₉ is N or CR₉;

X₁₀ is N or CR₁₀;

X₁₁ is N or CR₁₁;

each R is independently H or C₁-C₆ alkyl;

R_(1b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(2b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are defined as follows:

(i) R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

(ii) R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w); and R₆ andR₇, together with the carbon atoms to which they are attached, form aring of formula:

or

(iii) R₅ and R₆, together with the carbon atoms to which they areattached, form a ring of formula:

and

R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w):

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w); or R₁₂and R₁₃, together with the carbon atoms to which they are attached, forma ring of formula:

Y₁, Y₂, Z₁, and Z₂ are each independently O or C(R₁₄)₂;

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein when R₈ is H, then at least one of X₅, X₆, and X₇ is not N orCH;

wherein no more than two of X_(1b), X_(2b), X_(3b), and X_(4b) is N;

wherein no more than one of X₅, X₆, and X₇ is N;

wherein no more than one of X₉, X₁₀, and X₁₁ is N.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X_(1b) isN. In other embodiments, X_(1b) is CR_(1b).

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X_(2b) isN. In other embodiments, X_(2b) is CR_(2b).

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X_(3b) isN. In other embodiments, X_(3b) is CR_(3b).

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X_(4b) isN. In other embodiments, X_(4b) is CR_(4b).

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X₅ is N. Inother embodiments, X₅ is CR₅.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X₆ is N. Inother embodiments, X₆ is CR₆.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X₇ is N. Inother embodiments, X₇ is CR₇.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X₉ is N. Inother embodiments, X₉ is CR₉.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X₁₀ is N.In other embodiments, X₁₀ is CR₁₀.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein X₁₁ is N.In other embodiments, X₁₁ is CR₁₁.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein each R isindependently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R_(1b) isH, halo, or C₁-C₆ alkyl. In other embodiments, R_(1b) is halo or C₁-C₆alkyl. In other embodiments, R_(1b) is H or C₁-C₆ alkyl. In otherembodiments, R_(1b) is H or halo. In other embodiments, R_(1b) is halo.In other embodiments, R_(1b) is C₁-C₆ alkyl. In other embodiments,R_(1b) is H, F, or CH₃. In other embodiments, R_(1b) is H. In otherembodiments, R_(1b) is F. In other embodiments, R_(1b) is CH₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R_(2b) is Hor halo. In other embodiments, R_(2b) is halo. In other embodiments,R_(2b) is H or F. In other embodiments, R_(2b) is H. In otherembodiments, R_(2b) is F.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R_(3b) isH.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R_(4b) is Hor C₁-C₆ alkyl. In other embodiments, R_(4b) is C₁-C₆ alkyl. In otherembodiments, R_(4b) is H or CH₃. In other embodiments, R_(4b) is H. Inother embodiments, R_(4b) is CH₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₅ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,or C₁-C₆ alkoxy. In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, or C₁-C₆ alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆alkyl, or C₁-C₆ haloalkyl. In other embodiments, R₅ is halo. In otherembodiments, R₅ is C₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆haloalkyl. In other embodiments, R₅ is C₁-C₆ alkoxy. In otherembodiments, R₅ is H, F, Cl, CF₃, or OCH₃. In other embodiments, R₅ isH. In other embodiments, R₅ is F. In other embodiments, R₅ is Cl. Inother embodiments, R₅ is CF₃. In other embodiments, R₅ is OCH₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₆ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy. In other embodiments, R₆ is halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₆ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In otherembodiments, R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₆ is halo. In other embodiments, R₆ isC₁-C₆ alkyl. In other embodiments, R₆ is C₁-C₆ haloalkyl. In otherembodiments, R₆ is C₁-C₆ alkoxy. In other embodiments, R₆ is C₁-C₆haloalkoxy. In other embodiments, R₆ is H, F, Cl, OCHF₂, CF₃, CHF₂, orOCF₃. In other embodiments, R₆ is H. In other embodiments, R₆ is F. Inother embodiments, R₆ is Cl. In other embodiments, R₆ is OCHF₂. In otherembodiments, R₆ is CF₃. In other embodiments, R₆ is CHF₂. In otherembodiments, R₆ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₅ and R₆,together with the carbon atoms to which they are attached, form a ringof formula:

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₇ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w). In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy. In other embodiments, R₇ is halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₇ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In otherembodiments, R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₇ is halo. In other embodiments, R₇ isC₁-C₆ alkyl. In other embodiments, R₇ is C₁-C₆ haloalkyl. In otherembodiments, R₇ is C₁-C₆ alkoxy. In other embodiments, R₇ is C₁-C₆haloalkoxy. In other embodiments, R₇ is H, Cl, CF₃, OCHF₂, or OCF₃. Inother embodiments, R₇ is H. In other embodiments, R₇ is Cl. In otherembodiments, R₇ is CF₃. In other embodiments, R₇ is OCHF₂. In otherembodiments, R₇ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₆ and R₇,together with the carbon atoms to which they are attached, form a ringof formula:

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₈ is H.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₉ is H,C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkyl orC₁-C₆ alkoxy. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkyl. In other embodiments, R₉ is C₁-C₆ alkoxy. In other embodiments,R₉ is H, CH₃, or OCH₃. In other embodiments, R₉ is H. In otherembodiments, R₉ is ¹H. In other embodiments, R₉ is D. In otherembodiments, R₉ is CH₃. In other embodiments, R₉ is OCH₃. In otherembodiments, R₉ is OC(¹H)₃. In other embodiments, R₉ is OCD₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is H orhalo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ is Hor F. In other embodiments, R₁₀ is H. In other embodiments, R₁₀ is ¹H.In other embodiments, R₁₀ is D. In other embodiments, R₁₀ is F.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is F, Cl, or OCF₃. In other embodiments, R₁₁ is H. Inother embodiments, R₁₁ is ¹H. In other embodiments, R₁₁ is D. In otherembodiments, R₁₁ is F. In other embodiments, R₁₁ is Cl. In otherembodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₁₂ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₁₂ is H.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₁₃ is H,halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w). In other embodiments, R₁₃ is H.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein Y₁ is O,and Y₂ is C(R₁₄)₂. In other embodiments, Y₁ is C(R₁₄)₂, and Y₂ is O. Inother embodiments, Y₁ is O, and Y₂ is O. In other embodiments, Y₁ isC(R₁₄)₂, and Y₂ is C(R₁₄)₂.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein each R₁₄ isindependently H or F. In other embodiments, each R₁₄ is H. In otherembodiments, each R₁₄ is F.

In some embodiments, the invention relates to a compound of formula(II), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(II-A-1)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(1b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(2b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R_(1b)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(1b) is halo orC₁-C₆ alkyl. In other embodiments, R_(1b) is H or C₁-C₆ alkyl. In otherembodiments, R_(1b) is H or halo. In other embodiments, R_(1b) is halo.In other embodiments, R_(1b) is C₁-C₆ alkyl. In other embodiments,R_(1b) is H or F. In other embodiments, R_(1b) is H. In otherembodiments, R_(1b) is F.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R_(2b)is H or halo. In other embodiments, R_(2b) is halo. In otherembodiments, R_(2b) is H or F. In other embodiments, R_(2b) is H. Inother embodiments, R_(2b) is F.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R_(3b)is H.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R_(4b)is H or C₁-C₆ alkyl. In other embodiments, R_(4b) is C₁-C₆ alkyl. Inother embodiments, R_(4b) is H.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is halo orC₁-C₆ alkoxy. In other embodiments, R₅ is F or OCH₃. In otherembodiments, R₅ is F. In other embodiments, R₅ is OCH₃.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R₆ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₆ is halo. In other embodiments, R₆ is C₁-C₆ alkyl. Inother embodiments, R₆ is C₁-C₆ haloalkyl. In other embodiments, R₆ isC₁-C₆ alkoxy. In other embodiments, R₆ is C₁-C₆ haloalkoxy. In otherembodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R₇ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₇ is halo. In other embodiments, R₇ is C₁-C₆ alkyl. Inother embodiments, R₇ is C₁-C₆ haloalkyl. In other embodiments, R₇ isC₁-C₆ alkoxy. In other embodiments, R₇ is C₁-C₆ haloalkoxy. In otherembodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R₈ isH.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R₉ isH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkylor C₁-C₆ alkoxy. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkyl. In other embodiments, R₉ is C₁-C₆ alkoxy. In other embodiments,R₉ is H, CH₃, or OCH₃. In other embodiments, R₉ is H. In otherembodiments, R₉ is ¹H. In other embodiments, R₉ is D. In otherembodiments, R₉ is CH₃. In other embodiments, R₉ is OCH₃. In otherembodiments, R₉ is OC(¹H)₃. In other embodiments, R₉ is OCD₃.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH or halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀is H. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(II-A-1), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(II-A-1), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(II-A-2)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(1b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(2b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉ and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R_(1b)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(1b) is halo orC₁-C₆ alkyl. In other embodiments, R_(1b) is H or C₁-C₆ alkyl. In otherembodiments, R_(1b) is H or halo. In other embodiments, R_(1b) is halo.In other embodiments, R_(1b) is C₁-C₆ alkyl. In other embodiments,R_(1b) is H.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R_(2b)is H or halo. In other embodiments, R_(2b) is halo. In otherembodiments, R_(2b) is F.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R_(3b)is H.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R_(4b)is H or C₁-C₆ alkyl. In other embodiments, R_(4b) is C₁-C₆ alkyl. Inother embodiments, R_(4b) is H.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is F.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R₆ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₆ is halo. In other embodiments, R₆ is C₁-C₆ alkyl. Inother embodiments, R₆ is C₁-C₆ haloalkyl. In other embodiments, R₆ isC₁-C₆ alkoxy. In other embodiments, R₆ is C₁-C₆ haloalkoxy. In otherembodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R₇ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₇ is halo. In other embodiments, R₇ is C₁-C₆ alkyl. Inother embodiments, R₇ is C₁-C₆ haloalkyl. In other embodiments, R₇ isC₁-C₆ alkoxy. In other embodiments, R₇ is C₁-C₆ haloalkoxy. In otherembodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R₈ isH.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R₉ isH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkylor C₁-C₆ alkoxy. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkyl. In other embodiments, R₉ is C₁-C₆ alkoxy. In other embodiments,R₉ is H. In other embodiments, R₉ is ¹H. In other embodiments, R₉ is D.In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is Cl.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(II-A-2), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(II-A-2), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(II-B-1)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(1b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R_(1b)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(1b) is halo orC₁-C₆ alkyl. In other embodiments, R_(1b) is H or C₁-C₆ alkyl. In otherembodiments, R_(1b) is H or halo. In other embodiments, R_(1b) is halo.In other embodiments, R_(1b) is C₁-C₆ alkyl. In other embodiments,R_(1b) is H or CH₃. In other embodiments, R_(1b) is H. In otherembodiments, R_(1b) is CH₃.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R_(3b)is H.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R_(4b)is H or C₁-C₆ alkyl. In other embodiments, R_(4b) is C₁-C₆ alkyl. Inother embodiments, R_(4b) is H or CH₃. In other embodiments, R_(4b) isH. In other embodiments, R_(4b) is CH₃.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is H, F, Cl,CF₃, or OCH₃. In other embodiments, R₅ is H. In other embodiments, R₅ isF. In other embodiments, R₅ is Cl. In other embodiments, R₅ is CF₃. Inother embodiments, R₅ is OCH₃.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R₆ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₆ is halo. In other embodiments, R₆ is C₁-C₆ alkyl. Inother embodiments, R₆ is C₁-C₆ haloalkyl. In other embodiments, R₆ isC₁-C₆ alkoxy. In other embodiments, R₆ is C₁-C₆ haloalkoxy. In otherembodiments, R₆ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. Inother embodiments, R₆ is H, F, Cl, OCHF₂, CF₃, CHF₂, or OCF₃. In otherembodiments, R₆ is H. In other embodiments, R₆ is F. In otherembodiments, R₆ is Cl. In other embodiments, R₆ is OCHF₂. In otherembodiments, R₆ is CF₃. In other embodiments, R₆ is CHF₂. In otherembodiments, R₆ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R₇ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₇ is halo. In other embodiments, R₇ is C₁-C₆ alkyl. Inother embodiments, R₇ is C₁-C₆ haloalkyl. In other embodiments, R₇ isC₁-C₆ alkoxy. In other embodiments, R₇ is C₁-C₆ haloalkoxy. In otherembodiments, R₇ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. Inother embodiments, R₇ is H, Cl, CF₃, OCHF₂, or OCF₃. In otherembodiments, R₇ is H. In other embodiments, R₇ is Cl. In otherembodiments, R₇ is CF₃. In other embodiments, R₇ is OCHF₂. In otherembodiments, R₇ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R₈ isH.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R₉ isH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkylor C₁-C₆ alkoxy. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkyl. In other embodiments, R₉ is C₁-C₆ alkoxy. In other embodiments,R₉ is H or OCH₃. In other embodiments, R₉ is H. In other embodiments, R₉is ¹H. In other embodiments, R₉ is D. In other embodiments, R₉ is OCH₃.In other embodiments, R₉ is OC(¹H)₃. In other embodiments, R₉ is OCD₃.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH or halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀is H or F. In other embodiments, R₁₀ is H. In other embodiments, R₁₀ is¹H. In other embodiments, R₁₀ is D. In other embodiments, R₁₀ is F.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is F or OCF₃. In other embodiments, R₁₁ is H. In otherembodiments, R₁₁ is ¹H. In other embodiments, R₁₁ is D. In otherembodiments, R₁₁ is F. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(II-B-1), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(II-B-1), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(II-B-2)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(1b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each R₁₀ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R_(1b)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(1b) is halo orC₁-C₆ alkyl. In other embodiments, R_(1b) is H or C₁-C₆ alkyl. In otherembodiments, R_(1b) is H or halo. In other embodiments, R_(1b) is halo.In other embodiments, R_(1b) is C₁-C₆ alkyl. In other embodiments,R_(1b) is H.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R_(3b)is H.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R_(4b)is H or C₁-C₆ alkyl. In other embodiments, R_(4b) is C₁-C₆ alkyl. Inother embodiments, R_(4b) is H.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R₇ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₇ is halo. In other embodiments, R₇ is C₁-C₆ alkyl. Inother embodiments, R₇ is C₁-C₆ haloalkyl. In other embodiments, R₇ isC₁-C₆ alkoxy. In other embodiments, R₇ is C₁-C₆ haloalkoxy. In otherembodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R₈ isH.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R₉ isH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkylor C₁-C₆ alkoxy. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkyl. In other embodiments, R₉ is C₁-C₆ alkoxy. In other embodiments,R₉ is H. In other embodiments, R₉ is ¹H. In other embodiments, R₉ is D.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH or halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀is H. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(II-B-2), or a pharmaceutically acceptable salt thereof, wherein eachR₁₄ is independently H or F.

In some embodiments, the invention relates to a compound of formula(II-B-2), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(II-B-3)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(1b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅ and R₆ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R_(1b)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(1b) is halo orC₁-C₆ alkyl. In other embodiments, R_(1b) is H or C₁-C₆ alkyl. In otherembodiments, R_(1b) is H or halo. In other embodiments, R_(1b) is halo.In other embodiments, R_(1b) is C₁-C₆ alkyl. In other embodiments,R_(1b) is H.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R_(3b)is H.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R_(4b)is H or C₁-C₆ alkyl. In other embodiments, R_(4b) is C₁-C₆ alkyl. Inother embodiments, R_(4b) is H.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is halo orC₁-C₆ alkoxy. In other embodiments, R₅ is F or OCH₃. In otherembodiments, R₅ is F. In other embodiments, R₅ is OCH₃.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R₆ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₆ is halo. In other embodiments, R₆ is C₁-C₆ alkyl. Inother embodiments, R₆ is C₁-C₆ haloalkyl. In other embodiments, R₆ isC₁-C₆ alkoxy. In other embodiments, R₆ is C₁-C₆ haloalkoxy. In otherembodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R₈ isH.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R₉ isH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkylor C₁-C₆ alkoxy. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkyl. In other embodiments, R₉ is C₁-C₆ alkoxy. In other embodiments,R₉ is H. In other embodiments, R₉ is ¹H. In other embodiments, R₉ is D.In other embodiments, R₉ is OCH₃

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH or halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀is H. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(II-B-3), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(II-B-3), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(II-B-4)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(1b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R_(1b)is H, halo, or C₁-C₆ alkyl. In other embodiments, R_(1b) is halo orC₁-C₆ alkyl. In other embodiments, R_(1b) is H or C₁-C₆ alkyl. In otherembodiments, R_(1b) is H or halo. In other embodiments, R_(1b) is halo.In other embodiments, R_(1b) is C₁-C₆ alkyl. In other embodiments,R_(1b) is H.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R_(3b)is H.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R_(4b)is H or C₁-C₆ alkyl. In other embodiments, R_(4b) is C₁-C₆ alkyl. Inother embodiments, R_(4b) is H.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is H

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R₈ is H

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R₉ isH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkylor C₁-C₆ alkoxy. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkyl. In other embodiments, R₉ is C₁-C₆ alkoxy. In other embodiments,R₉ is H. In other embodiments, R₉ is ¹H. In other embodiments, R₉ is D.In other embodiments, R₉ is OCH₃.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH or halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀is H. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(II-B-4), or a pharmaceutically acceptable salt thereof, wherein eachR₁₄ is F.

In some embodiments, the invention relates to a compound of formula(II-B-4), i.e., the compound in non-salt form.

In another aspect, the invention relates to a compound of formula(II-B-5)

or a pharmaceutically acceptable salt thereof, wherein:

L is O, C(R)₂, or a single bond;

each R is independently H or C₁-C₆ alkyl;

R_(2b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy;

R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w);

R₈ is H or —O—(CH₂)_(n)—R_(w);

R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);

each W is independently O or a single bond;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; and

n is 0 or 1;

wherein at least one of R₅, R₆, R₇, and R₈ is not H.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein each Ris independently H or CH₃. In other embodiments, each R is H. In otherembodiments, each R is CH₃.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R_(2b)is H or halo. In other embodiments, R_(2b) is halo. In otherembodiments, R_(2b) is H.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R_(3b)is H.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R_(4b)is H or C₁-C₆ alkyl. In other embodiments, R_(4b) is C₁-C₆ alkyl. Inother embodiments, R_(4b) is H.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R₅ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₅ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy.In other embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆alkoxy. In other embodiments, R₅ is H, halo, C₁-C₆ alkyl, or C₁-C₆haloalkyl. In other embodiments, R₅ is halo. In other embodiments, R₅ isC₁-C₆ alkyl. In other embodiments, R₅ is C₁-C₆ haloalkyl. In otherembodiments, R₅ is C₁-C₆ alkoxy. In other embodiments, R₅ is halo orC₁-C₆ alkoxy. In other embodiments, R₅ is F or OCH₃. In otherembodiments, R₅ is F. In other embodiments, R₅ is OCH₃.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R₆ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₆ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₆ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₆ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₆ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₆ is halo. In other embodiments, R₆ is C₁-C₆ alkyl. Inother embodiments, R₆ is C₁-C₆ haloalkyl. In other embodiments, R₆ isC₁-C₆ alkoxy. In other embodiments, R₆ is C₁-C₆ haloalkoxy. In otherembodiments, R₆ is CF₃.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R₇ isH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy. In other embodiments, R₇ is halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₇ is H, halo, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₇ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In other embodiments,R₇ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ alkoxy. In otherembodiments, R₇ is halo. In other embodiments, R₇ is C₁-C₆ alkyl. Inother embodiments, R₇ is C₁-C₆ haloalkyl. In other embodiments, R₇ isC₁-C₆ alkoxy. In other embodiments, R₇ is C₁-C₆ haloalkoxy. In otherembodiments, R₇ is H.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R₈ isH.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R₉ isH, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkylor C₁-C₆ alkoxy. In other embodiments, R₉ is H or C₁-C₆ alkoxy. In otherembodiments, R₉ is H or C₁-C₆ alkyl. In other embodiments, R₉ is C₁-C₆alkyl. In other embodiments, R₉ is C₁-C₆ alkoxy. In other embodiments,R₉ is H. In other embodiments, R₉ is ¹H. In other embodiments, R₉ is D.In other embodiments, R₉ is OCH₃. In other embodiments, R₉ is OC(¹H)₃.In other embodiments, R₉ is OCD₃.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH or halo. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀is H. In other embodiments, R₁₀ is ¹H. In other embodiments, R₁₀ is D.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ isC₁-C₆ alkoxy or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo orC₁-C₆ haloalkoxy. In other embodiments, R₁₁ is halo or C₁-C₆ alkoxy. Inother embodiments, R₁₁ is halo. In other embodiments, R₁₁ is C₁-C₆alkoxy. In other embodiments, R₁₁ is C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H. In other embodiments, R₁₁ is ¹H. In otherembodiments, R₁₁ is D. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula(II-B-5), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula(II-B-5), i.e., the compound in non-salt form.

In some embodiments, the invention relates to a compound selected fromTable 1, 1A, or 1B, or a pharmaceutically acceptable salt thereof. Inother embodiments, the invention relates to a compound selected fromTable 1, 1A, or 1B, i.e., the compound in non-salt form.

TABLE 1 Compound Numbers, Structures, and Chemical Names Compound NumberCompound Structure and Chemical Name 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE 1A Compound Numbers and Structures.

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

TABLE 1B Compound Numbers and Structures.

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

292

293

294

295

296

297

298

299

300

301

302

303

In some embodiments, the invention relates to the compound identified inTable 1C, or a pharmaceutically acceptable salt thereof. In otherembodiments, the invention relates to the compound identified in Table1C, i.e., the compound in non-salt form.

Table 1C. Compound Number and Structure.

Salts, Compositions, Uses, Formulation, Administration and AdditionalAgents Pharmaceutically Acceptable Salts and Compositions

As discussed herein, the invention provides compounds, andpharmaceutically acceptable salts thereof, that are inhibitors ofvoltage-gated sodium channels, and thus the present compounds, andpharmaceutically acceptable salts thereof, are useful for the treatmentof diseases, disorders, and conditions including, but not limited tochronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain(e.g., bunionectomy pain or abdominoplasty pain), visceral pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence,pathological cough, or cardiac arrhythmia. Accordingly, in anotheraspect of the invention, pharmaceutical compositions are provided,wherein these compositions comprise a compound as described herein, or apharmaceutically acceptable salt thereof, and optionally comprise apharmaceutically acceptable carrier, adjuvant or vehicle. In certainembodiments, these compositions optionally further comprise one or moreadditional therapeutic agents. In some embodiments, the additionaltherapeutic agent is a sodium channel inhibitor.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” of a compound of this inventionincludes any non-toxic salt that, upon administration to a recipient, iscapable of providing, either directly or indirectly, a compound of thisinvention or an inhibitorily active metabolite or residue thereof. Thesalt may be in pure form, in a mixture (e.g., solution, suspension, orcolloid) with one or more other substances, or in the form of a hydrate,solvate, or co-crystal. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As described herein, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical compositioncomprising a compound of the invention, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention features a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject a compound of the invention or a pharmaceutically acceptablesalt thereof or a pharmaceutical composition thereof. In another aspect,the voltage-gated sodium channel is Nav1.8.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomy painor abdominoplasty pain), visceral pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, pathological cough, orcardiac arrhythmia comprising administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain, bunionectomy pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, orcardiac arrhythmia comprising administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain wherein said method comprises administeringan effective amount of a compound of the invention, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the neuropathic pain comprises post-herpeticneuralgia or idiopathic small-fiber neuropathy. As used herein, thephrase “idiopathic small-fiber neuropathy” shall be understood toinclude any small fiber neuropathy.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain, whereinneuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma;traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerveavulsion injury, brachial plexus avulsion injury; complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia; post spinal cordinjury pain, idiopathic small-fiber neuropathy, idiopathic sensoryneuropathy or trigeminal autonomic cephalalgia wherein said methodcomprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the musculoskeletal pain comprisesosteoarthritis pain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain, whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, coldpain, burn pain or dental pain wherein said method comprisesadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain or vulvodyniawherein said method comprises administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain wherein saidmethod comprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of idiopathic pain, whereinidiopathic pain comprises fibromyalgia pain wherein said methodcomprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of pathological cough wherein saidmethod comprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the acute pain comprises acute post-operativepain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of postsurgical pain (e.g.,bunionectomy pain or abdominoplasty pain) comprising administering aneffective amount of a compound of the invention, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of bunionectomy pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of abdominoplasty pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of visceral pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the visceral pain comprises visceral pain fromabdominoplasty.

In yet another aspect, the invention features a method wherein thesubject is treated with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith an effective amount of the compound, pharmaceutically acceptablesalt or pharmaceutical composition. In some embodiments, the additionaltherapeutic agent is a sodium channel inhibitor.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a biological sample comprisingcontacting the biological sample with an effective amount of a compoundof the invention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof. In another aspect, the voltage-gatedsodium channel is Nav1.8.

In another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain, chronic pain,neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, pathological cough,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head pain, neck pain,severe pain, intractable pain, nociceptive pain, breakthrough pain,postsurgical pain (e.g., bunionectomy pain or abdominoplasty pain),cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility, comprising administering an effective amount of a compound ofthe invention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In another aspect, the invention features a method of treating orlessening the severity in a subject of femur cancer pain; non-malignantchronic bone pain; rheumatoid arthritis; osteoarthritis; spinalstenosis; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic pain; IBS pain; chronic and acute headachepain; migraine; tension headache; cluster headaches; chronic and acuteneuropathic pain, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Toothneuropathy; hereditary sensory neuropathy; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury pain; exercise pain; acute visceral pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain; acute inflammatorypain, burn pain, trauma pain; acute intermittent pain, endometriosis;acute herpes zoster pain; sickle cell anemia; acute pancreatitis;breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiplesclerosis (MS) pain; pain in depression; leprosy pain; Behcet's diseasepain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painfullegs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry'sdisease pain; bladder and urogenital disease; urinary incontinence,pathological cough; hyperactive bladder; painful bladder syndrome;interstitial cystitis (IC); prostatitis; complex regional pain syndrome(CRPS), type I, complex regional pain syndrome (CRPS) type II;widespread pain, paroxysmal extreme pain, pruritus, tinnitus, orangina-induced pain, comprising administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use as a medicament.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of inhibiting a voltage-gated sodiumchannel in a subject. In another aspect, the voltage-gated sodiumchannel is Nav1.8.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of chronic pain, gut pain, neuropathic pain, musculoskeletalpain, acute pain, inflammatory pain, cancer pain, idiopathic pain,postsurgical pain (e.g., bunionectomy pain or abdominoplasty pain),visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome,incontinence, pathological cough, or cardiac arrhythmia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of chronic pain, gut pain, neuropathic pain, musculoskeletalpain, acute pain, inflammatory pain, cancer pain, idiopathic pain,postsurgical pain, bunionectomy pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of gut pain, wherein gut pain comprises inflammatory boweldisease pain, Crohn's disease pain or interstitial cystitis pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of neuropathic pain. In some aspects, the neuropathic paincomprises post-herpetic neuralgia or idiopathic small-fiber neuropathy.As used herein, the phrase “idiopathic small-fiber neuropathy” shall beunderstood to include any small fiber neuropathy.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of neuropathic pain, wherein neuropathic pain comprisespost-herpetic neuralgia, diabetic neuralgia, painful HIV-associatedsensory neuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma; traumatic neuroma;Morton's neuroma; nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury,brachial plexus avulsion injury; complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia; post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of musculoskeletal pain. In some aspects, the musculoskeletalpain comprises osteoarthritis pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of musculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of inflammatory pain, wherein inflammatory pain comprisesrheumatoid arthritis pain or vulvodynia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of inflammatory pain, wherein inflammatory pain comprisesrheumatoid arthritis pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of idiopathic pain, wherein idiopathic pain comprisesfibromyalgia pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of pathological cough.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of acute pain. In some aspects, the acute pain comprises acutepost-operative pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of postsurgical pain (e.g., bunionectomy pain or abdominoplastypain).

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of bunionectomy pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of abdominoplasty pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of visceral pain. In some aspects, the visceral pain comprisesvisceral pain from abdominoplasty.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method wherein the subject is treated with one ormore additional therapeutic agents administered concurrently with, priorto, or subsequent to treatment with an effective amount of the compound,pharmaceutically acceptable salt or pharmaceutical composition. In someembodiments, the additional therapeutic agent is a sodium channelinhibitor.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of inhibiting a voltage-gated sodiumchannel in a biological sample comprising contacting the biologicalsample with an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In another aspect, the voltage-gated sodium channel is Nav1.8.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of acute pain, chronic pain, neuropathic pain, inflammatorypain, arthritis, migraine, cluster headaches, trigeminal neuralgia,herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions,neurodegenerative disorders, psychiatric disorders, anxiety, depression,bipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, pathological cough, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head pain, neck pain, severe pain,intractable pain, nociceptive pain, breakthrough pain, postsurgical pain(e.g., bunionectomy pain or abdominoplasty pain), cancer pain, stroke,cerebral ischemia, traumatic brain injury, amyotrophic lateralsclerosis, stress induced angina, exercise induced angina, palpitations,hypertension, or abnormal gastro-intestinal motility.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; myofascial pain syndrome; fibromyalgia; temporomandibularjoint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBSpain; chronic and acute headache pain; migraine; tension headache;cluster headaches; chronic and acute neuropathic pain, post-herpeticneuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminalneuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensoryneuropathy; peripheral nerve injury; painful neuromas; ectopic proximaland distal discharges; radiculopathy; chemotherapy induced neuropathicpain; radiotherapy-induced neuropathic pain; post-mastectomy pain;central pain; spinal cord injury pain; post-stroke pain; thalamic pain;complex regional pain syndrome; phantom pain; intractable pain; acutepain, acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury pain; exercisepain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain,renal colic pain, acute obstetric pain, labor pain; cesarean sectionpain; acute inflammatory pain, burn pain, trauma pain; acuteintermittent pain, endometriosis; acute herpes zoster pain; sickle cellanemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitispain; dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease; urinary incontinence, pathological cough; hyperactive bladder;painful bladder syndrome; interstitial cystitis (IC); prostatitis;complex regional pain syndrome (CRPS), type I, complex regional painsyndrome (CRPS) type II; widespread pain, paroxysmal extreme pain,pruritus, tinnitus, or angina-induced pain.

Manufacture of Medicaments

In another aspect, the invention provides the use of a compound of theinvention, or a pharmaceutically acceptable salt or pharmaceuticalcomposition thereof, for the manufacture of a medicament.

In another aspect, the invention provides the use of a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in inhibiting a voltage-gated sodium channel. In another aspect,the voltage-gated sodium channel is Nav1.8.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of chronicpain, gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, postsurgical pain(e.g., bunionectomy pain or abdominoplasty pain), visceral pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence,pathological cough, or cardiac arrhythmia.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of chronicpain, gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, postsurgical pain,bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome,incontinence, or cardiac arrhythmia.

In yet another aspect, the invention provides the use of the compound,pharmaceutically acceptable salt, or pharmaceutical compositiondescribed herein for the manufacture of a medicament for use in treatingor lessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain.

In yet another aspect, the invention provides a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofneuropathic pain. In some aspects, the neuropathic pain comprisespost-herpetic neuralgia or idiopathic small-fiber neuropathy.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in a treating or lessening the severity in a subject ofneuropathic pain, wherein neuropathic pain comprises post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma; traumatic neuroma;Morton's neuroma; nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury,brachial plexus avulsion injury; complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia; post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic neuropathy.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofmusculoskeletal pain. In some aspects the musculoskeletal pain comprisesosteoarthritis pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofmusculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofinflammatory pain, wherein inflammatory pain comprises rheumatoidarthritis pain or vulvodynia.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofinflammatory pain, wherein inflammatory pain comprises rheumatoidarthritis pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of idiopathicpain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofpathological cough.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of acutepain. In some aspects, the acute pain comprises acute post-operativepain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofpostsurgical pain (e.g., bunionectomy pain or abdominoplasty pain).

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofbunionectomy pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofabdominoplasty pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of visceralpain. In some aspects, the visceral pain comprises visceral pain fromabdominoplasty.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in combination with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith the compound or pharmaceutical composition. In some embodiments,the additional therapeutic agent is a sodium channel inhibitor.

In another aspect, the invention provides the use of a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity of acute pain, chronicpain, neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, pathological cough,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head pain, neck pain,severe pain, intractable pain, nociceptive pain, breakthrough pain,postsurgical pain (e.g., bunionectomy pain or abdominoplasty pain),cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility.

In another aspect, the invention provides the use of a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity of femur cancer pain;non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis;spinal stenosis; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic pain; IBS pain; chronic and acute headachepain; migraine; tension headache; cluster headaches; chronic and acuteneuropathic pain, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Toothneuropathy; hereditary sensory neuropathy; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury pain; exercise pain; acute visceral pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain; acute inflammatory,burn pain, trauma pain; acute intermittent pain, endometriosis; acuteherpes zoster pain; sickle cell anemia; acute pancreatitis; breakthroughpain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis(MS) pain; pain in depression; leprosy pain; Behcet's disease pain;adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs andmoving toes; Haglund syndrome; erythromelalgia pain; Fabry's diseasepain; bladder and urogenital disease; urinary incontinence; pathologicalcough; hyperactive bladder; painful bladder syndrome; interstitialcystitis (IC); prostatitis; complex regional pain syndrome (CRPS) typeI; complex regional pain syndrome (CRPS) type II; widespread pain,paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

Administration of Pharmaceutically Acceptable Salts and Compositions.

In certain embodiments of the invention an “effective amount” of acompound of the invention, a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof is that amount effective fortreating or lessening the severity of one or more of the conditionsrecited above.

The compounds, salts, and compositions, according to the method of theinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of the pain or non-pain diseases recited herein. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of thecondition, the particular agent, its mode of administration, and thelike. The compounds, salts, and compositions of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thesubject to be treated. It will be understood, however, that the totaldaily usage of the compounds, salts, and compositions of the inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularsubject or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound or salt employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thesubject; the time of administration, route of administration, and rateof excretion of the specific compound or salt employed; the duration ofthe treatment; drugs used in combination or coincidental with thespecific compound or salt employed, and like factors well known in themedical arts. The term “subject” or “patient,” as used herein, means ananimal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the condition being treated. Incertain embodiments, the compound, salts, and compositions of theinvention may be administered orally or parenterally at dosage levels ofabout 0.001 mg/kg to about 100 mg/kg, or about 0.01 mg/kg to about 50mg/kg, of subject body weight per day, one or more times a day,effective to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compound orsalt, the liquid dosage forms may contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of the compounds of the invention, it isoften desirable to slow the absorption of the compounds fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compound or salt ofthis invention with suitable non-irritating excipients or carriers suchas cocoa butter, polyethylene glycol or a suppository wax which aresolid at ambient temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the activecompound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound or salt is mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and silicic acid, b) binders such as, forexample, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such asglycerol, d) disintegrating agents such as agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates, and sodiumcarbonate, e) solution retarding agents such as paraffin, f) absorptionaccelerators such as quaternary ammonium compounds, g) wetting agentssuch as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and i) lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case of capsules,tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compound or salt can also be in microencapsulated form withone or more excipients as noted above. The solid dosage forms oftablets, dragees, capsules, pills, and granules can be prepared withcoatings and shells such as enteric coatings, release controllingcoatings and other coatings well known in the pharmaceutical formulatingart. In such solid dosage forms the active compound or salt may beadmixed with at least one inert diluent such as sucrose, lactose orstarch. Such dosage forms may also comprise, as is normal practice,additional substances other than inert diluents, e.g., tabletinglubricants and other tableting aids such a magnesium stearate andmicrocrystalline cellulose. In the case of capsules, tablets and pills,the dosage forms may also comprise buffering agents. They may optionallycontain opacifying agents and can also be of a composition that theyrelease the active ingredient(s) only, or preferentially, in a certainpart of the intestinal tract, optionally, in a delayed manner. Examplesof embedding compositions that can be used include polymeric substancesand waxes.

Dosage forms for topical or transdermal administration of a compound orsalt of this invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium channels. In one embodiment, thecompounds are inhibitors of Na_(V)1.8 and thus, without wishing to bebound by any particular theory, the compounds, salts, and compositionsare particularly useful for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity ofNa_(V)1.8 is implicated in the disease, condition, or disorder. Whenactivation or hyperactivity of Na_(V)1.8 is implicated in a particulardisease, condition, or disorder, the disease, condition, or disorder mayalso be referred to as a “Na_(V)1.8-mediated disease, condition ordisorder.”Accordingly, in another aspect, the invention provides amethod for treating or lessening the severity of a disease, condition,or disorder where activation or hyperactivity of Na_(V)1.8 is implicatedin the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNa_(V)1.8 may be assayed according to methods described generally inInternational Publication No. WO 2014/120808 A9 and U.S. Publication No.2014/0213616 A1, both of which are incorporated by reference in theirentirety, methods described herein, and other methods known andavailable to one of ordinary skill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds, salts, andpharmaceutically acceptable compositions of the invention can beemployed in combination therapies, that is, the compounds, salts, andpharmaceutically acceptable compositions can be administeredconcurrently with, prior to, or subsequent to, one or more other desiredtherapeutics or medical procedures. The particular combination oftherapies (therapeutics or procedures) to employ in a combinationregimen will take into account compatibility of the desired therapeuticsand/or procedures and the desired therapeutic effect to be achieved. Itwill also be appreciated that the therapies employed may achieve adesired effect for the same disorder (for example, an inventive compoundmay be administered concurrently with another agent used to treat thesame disorder), or they may achieve different effects (e.g., control ofany adverse effects). As used herein, additional therapeutic agents thatare normally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.” For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blockade), neurosurgical (neurolysis ofCNS pathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, NineteenthEdition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & DohmeCorp., a subsidiary of Merck & Co., Inc., 2011, and the Food and DrugAdministration website, www.fda.gov, the entire contents of which arehereby incorporated by reference.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

(1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl,cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene,nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,nalbuphine, pentazocine, or difelikefalin;

(2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal,flurbiprofen, ibuprofen (including without limitation intravenousibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac(including without limitation ketorolac tromethamine (e.g., Toradol®)),meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, e.g. amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, metharbital, methohexital,pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal orthiopental;

(4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide,clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam ortriazolam;

(5) a histamine (Hi) antagonist having a sedative action, e.g.diphenhydramine, pyrilamine, promethazine, chlorpheniramine orchlorcyclizine;

(6) a sedative such as glutethimide, meprobamate, methaqualone ordichloralphenazone;

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

(8) an NMDA receptor antagonist, e.g. dextromethorphan((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinolinequinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,EN-3231 (MorphiDex®), a combination formulation of morphine anddextromethorphan), topiramate, neramexane or perzinfotel including anNR2B antagonist, e.g. ifenprodil, traxoprodil or(−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,guanfacine, dexmedetomidine, modafinil, or4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine,amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine,topiramate, lacosamide (Vimpat®) or valproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g.(alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

(13) a muscarinic antagonist, e.g. oxybutynin, tolterodine, propiverine,tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgesic, in particular paracetamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol,perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine,clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole,aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone,raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride,balaperidone, palindore, eplivanserin, osanetant, rimonabant,meclinertant, Miraxion® or sarizotan;

(17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) orantagonist (e.g. capsazepine, GRC-15300);

(18) a beta-adrenergic such as propranolol;

(19) a local anaesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly a 5-HT_(1B/1D)agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan orrizatriptan;

(22) a 5-HT_(2A) receptor antagonist such asR(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol(MDL-100907);

(23) a cholinergic (nicotinic) analgesic, such as ispronicline(TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403),(R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);

(25) a PDE5 inhibitor, such as5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione(IC-351 or tadalafil),2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(vardenafil),5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-O-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

(26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentinGR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®),3-methyl gabapentin,(1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,(3S,5R)-3-aminomethyl-5-methyl-octanoic acid,(3S,5R)-3-amino-5-methyl-nonanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

(27) a cannabinoid such as KHK-6188;

(28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;

(29) a serotonin reuptake inhibitor such as sertraline, sertralinemetabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetinedesmethyl metabolite), fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,l-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine and trazodone;

(30) a noradrenaline (norepinephrine) reuptake inhibitor, such asmaprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion,nomifensine and viloxazine (Vivalan®), especially a selectivenoradrenaline reuptake inhibitor such as reboxetine, in particular(S,S)-reboxetine;

(31) a dual serotonin-noradrenaline reuptake inhibitor, such asvenlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine(Cymbalta®), milnacipran and imipramine;

(32) an inducible nitric oxide synthase (iNOS) inhibitor such asS-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile;2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,(2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,NXN-462, or guanidinoethyldisulfide;

(33) an acetylcholinesterase inhibitor such as donepezil;

(34) a prostaglandin E2 subtype 4 (EP4) antagonist such asN-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamideor4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoicacid;

(35) a leukotriene B4 antagonist; such as1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylicacid (CP-105696),5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valericacid (ONO-4057) or DPC-11870;

(36) a 5-lipoxygenase inhibitor, such as zileuton,6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone(ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone(CV-6504);

(37) a sodium channel blocker, such as lidocaine, lidocaine plustetracaine cream (ZRS-201) or eslicarbazepine acetate;

(38) an Na_(V)1.7 blocker, such as XEN-402, XEN403, TV-45070,PF-05089771, CNV1014802, GDC-0276, RG7893 and such as those disclosed inWO2011/140425 (US2011/306607); WO2012/106499 (US2012196869);WO2012/112743 (US2012245136); WO2012/125613 (US2012264749),WO2012/116440 (US2014187533), WO2011026240 (US2012220605), U.S. Pat. No.8,883,840, U.S. Pat. No. 8,466,188, or WO2013/109521 (US2015005304), theentire contents of each application hereby incorporated by reference.

(38a) an Na_(V)1.7 blocker such as(2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl)-(4-isopropoxy-3-methyl-phenyl)methanone,2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone,1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxylpropan-2-ol,(4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone,(4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carbonyl]phenyl]pyridine-2-carbonitrile,(4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,(4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,1-[(3S)-2,3-dimethyl-1′-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2,2-trifluoro-ethanone,[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone,2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,1-[1′-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2-dimethyl-propan-1-one,(4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,[2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone,4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyllbenzamideor(3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone.

(39) an Na_(V)1.8 blocker, such as PF-04531083, PF-06372865 and such asthose disclosed in WO2008/135826 (US2009048306), WO2006/011050(US2008312235), WO2013/061205 (US2014296313), US20130303535,WO2013131018, U.S. Pat. No. 8,466,188, WO2013114250 (US2013274243),WO2014/120808 (US2014213616), WO2014/120815 (US2014228371) WO2014/120820(US2014221435), WO2015/010065 (US20160152561), and WO2015/089361(US20150166589), the entire contents of each application herebyincorporated by reference.

(39a) an Na_(V)1.8 blocker such as4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide,4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide,5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide,2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide,2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,In one embodiment, the compound is3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide,3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid,2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide,3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide,N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide,3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid,3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide,3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide,3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoicacid,N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid,5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoicacid,5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid,4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoicacid,5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinicacid,4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoicacid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinicacid,4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoicacid,4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoicacid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoicacid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoicacid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinicacid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinicacid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoicacid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid,5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid,5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid,4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid,5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid,2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide,2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide,2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide,2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide,5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide orN-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide.

(40) a combined Na_(V)1.7 and Na_(V)1.8 blocker, such as DSP-2230 orBL-1021;

(41) a 5-HT3 antagonist, such as ondansetron;

(42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®,Qutenza®); and the pharmaceutically acceptable salts and solvatesthereof;

(43) a nicotinic receptor antagonist, such as varenicline;

(44) an N-type calcium channel antagonist, such as Z-160;

(45) a nerve growth factor antagonist, such as tanezumab;

(46) an endopeptidase stimulant, such as senrebotase;

(47) an angiotensin II antagonist, such as EMA-401;

(48) acetaminophen (including without limitation intravenousacetaminophen (e.g., Ofirmev®));

(49) bupivacaine (including without limitation bupivacaine liposomeinjectable suspension (e.g., Exparel®) and transdermal bupivacaine(Eladur®)); and

(50) bupivacaine and meloxicam combination (e.g., HTX-011).

In one embodiment, the additional appropriate therapeutic agents areselected from V-116517, Pregabalin, controlled release Pregabalin,Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®),AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine(Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 orARC-4558.

In another embodiment, the additional appropriate therapeutic agents areselected fromN-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide;N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide;or3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

In another embodiment, the additional therapeutic agent is a sodiumchannel inhibitor (also know as a sodium channel blocker), such as theNa_(V)1.7 and Na_(V)1.8 blockers identified above.

The amount of additional therapeutic agent present in the compositionsof this invention may be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. The amount of additional therapeutic agent in thepresently disclosed compositions may range from about 10% to 100% of theamount normally present in a composition comprising that agent as theonly therapeutically active agent.

The compounds and salts of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound or salt of the invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the invention includes an implantable device coated with acomposition comprising a compound or salt of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. Suitable coatings and thegeneral preparation of coated implantable devices are described in U.S.Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Na_(V)1.8 activityin a biological sample or a subject, which method comprisesadministering to the subject, or contacting said biological sample witha compound of the invention, a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof. The term “biological sample,”as used herein, includes, without limitation, cell cultures or extractsthereof; biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof.

Inhibition of Na_(V)1.8 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumchannels in biological and pathological phenomena; and the comparativeevaluation of new sodium channel inhibitors.

Synthesis of the Compounds of the Invention

The compounds of the invention can be prepared from known materials bythe following methods, similar methods, and other methods known to oneskilled in the art. As one skilled in the art would appreciate, thefunctional groups of the intermediate compounds in the methods describedbelow may need to be protected by suitable protecting groups. Protectinggroups may be added or removed in accordance with standard techniques,which are well-known to those skilled in the art. The use of protectinggroups is described in detail in T. G. M. Wuts et al., Greene'sProtective Groups in Organic Synthesis (4th ed. 2006).

In general, the compounds of formula (I-A) where L is O can besynthesized according to the general methods outlined in Scheme 1 andthe specific procedures discussed in the Examples. The startingmaterials for the synthesis described in Scheme 1 are commerciallyavailable or can be prepared according to methods known to one skilledin the art.

In general, the compounds of formulas (I-B) and (II) where L is O can besynthesized by methods analogous to the general methods outlined inScheme 1, and by the specific procedures discussed in the Examples.

In general, the compounds of formula (I-A) where L is a single bond canbe synthesized according to the general methods outlined in Scheme 2 andthe specific procedures discussed in the Examples. The startingmaterials for the synthesis described in Scheme 2 are commerciallyavailable or can be prepared according to methods known to one skilledin the art.

In general, the compounds of formulas (I-B) and (II) where L is a singlebond can be synthesized by methods analogous to the general methodsoutlined in Scheme 2, and by the specific procedures discussed in theExamples.

In general, the compounds of formula (I-A) where L is CR₂ can besynthesized according to the general methods outlined in Scheme 3. Thestarting materials for the synthesis described in Scheme 3 arecommercially available or can be prepared according to methods known toone skilled in the art.

In general, the compounds of formulas (I-B) and (II) where L is CR₂ canbe synthesized by methods analogous to the general methods outlined inScheme 3.

Radiolabeled Analogs of the Compounds of the Invention

In another aspect, the invention relates to radiolabeled analogs of thecompounds of the invention. As used herein, the term “radiolabeledanalogs of the compounds of the invention” refers to compounds that areidentical to the compounds of the invention, including the compounds offormulas (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6),(I-A-7), (I-A-8), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-B-5),(I-B-6), (I-B-7), (I-B-8), (I-B-9), (I-B-10), (II), (II-A-1), (II-A-2),(II-B-1), (II-B-2), (II-B-3), (II-B-4), and (II-B-5), and all of theembodiments thereof, as described herein, and the compounds identifiedin Tables 1, 1A, 1B, and 1C, except that one or more atoms has beenreplaced with a radioisotope of the atom present in the compounds of theinvention.

As used herein, the term “radioisotope” refers to an isolope of anelement that is known to undergo spontaneous radioactive decay. Examplesof radioisotopes include ³H, ¹⁴C, ³²F, ³⁵S, ¹⁸F, ³⁶Cl, and the like, aswell as the isotopes for which no decay mode is identified in V. S.Shirley & C. M. Lederer, Isotopes Project, Nuclear Science Division,Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

The radiolabeled analogs can be used in a number of beneficial ways,including in various types of assays, such as substrate tissuedistribution assays. For example, tritium (³H)- and/or carbon-14(¹⁴C)-labelled compounds are particularly useful for various types ofassays, such as substrate tissue distribution assays, due to relativelysimple preparation and excellent detectability.

In another aspect, the invention relates to pharmaceutically acceptablesalts of the radiolabeled analogs, in accordance with any of theembodiments described herein in connection with the compounds of theinvention.

In another aspect, the invention relates to pharmaceutical compositionscomprising the radiolabeled analogs, or pharmaceutically acceptablesalts thereof, and a pharmaceutically acceptable carrier, adjuvant orvehicle, in accordance with any of the embodiments described herein inconnection with the compounds of the invention.

In another aspect, the invention relates to methods of inhibitingvoltage-gated sodium channels and methods of treating or lessening theseverity of various diseases and disorders, including pain, in a subjectcomprising administering an effective amount of the radiolabeledanalogs, pharmaceutically acceptable salts thereof, and pharmaceuticalcompositions thereof, in accordance with any of the embodimentsdescribed herein in connection with the compounds of the invention.

In another aspect, the invention relates to radiolabeled analogs,pharmaceutically acceptable salts thereof, and pharmaceuticalcompositions thereof, for use, in accordance with any of the embodimentsdescribed herein in connection with the compounds of the invention.

In another aspect, the invention relates to the use of the radiolabeledanalogs, or pharmaceutically acceptable salts thereof, andpharmaceutical compositions thereof, for the manufacture of medicaments,in accordance with any of the embodiments described herein in connectionwith the compounds of the invention.

In another aspect, the radiolabeled analogs, pharmaceutically acceptablesalts thereof, and pharmaceutical compositions thereof, can be employedin combination therapies, in accordance with any of the embodimentsdescribed herein in connection with the compounds of the invention.

EXAMPLES

General Methods.

¹H NMR (400 MHz) spectra were obtained as solutions in an appropriatedeuterated solvent such as dimethyl sulfoxide-d₆ (DMSO-d6).

Compound purity, retention time, and electrospray mass spectrometry(ESI-MS) data were determined by LC/MS analysis using one of 9 methods:Methods A-I.

LC/MS Method A. LC/MS analysis was conducted using a Waters AcquityUltra Performance LC system by reverse phase UPLC using an Acquity UPLCBEH C18 column (30×2.1 mm, 1.7 μm particle) made by Waters (pn:186002349), and a dual gradient run from 1-99% mobile phase B over 1.2minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phase B═CH₃CN(0.035% CF₃CO₂H). Flow rate=1.5 mL/min, injection volume=1.5 μL, andcolumn temperature=60° C.

LC/MS Method B. LC/MS analysis was conducted using a Waters AcquityUltra Performance LC system by reverse phase UPLC using an Acquity UPLCBEH C₁₈ column (50×2.1 mm, 1.7 μm particle) made by Waters (pn:186002350), and a dual gradient run from 1-99% mobile phase B over 3.0minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phase B═CH₃CN(0.035% CF₃CO₂H). Flow rate=1.2 mL/min, injection volume=1.5 μL, andcolumn temperature=60° C.

LC/MS Method C. LC/MS analysis was conducted using a Waters AcquityUltra Performance LC system by reverse phase UPLC using an Acquity UPLCBEH C₁₈ column (50×2.1 mm, 1.7 μm particle) made by Waters (pn:186002350), and a dual gradient run from 1-99% mobile phase B over 5.0minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phase B═CH₃CN(0.035% CF₃CO₂H). Flow rate=1.2 mL/min, injection volume=1.5 μL, andcolumn temperature=60° C.

LC/MS Method D. LC/MS analysis was conducted using an Acquity UPLC BEHC₈ column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877)with a (2.1×5 mm, 1.7 μm particle) guard column (pn: 186003978), and adual gradient run from 2-98% mobile phase B over 1.15 minutes. Mobilephase A=H₂O (10 mM ammonium formate with 0.05% ammonium hydroxide).Mobile phase B=acetonitrile. Flow rate=1.0 mL/min, injection volume=2μL, and column temperature=45° C.

LC/MS Method E. LC/MS analysis was conducted using an Acquity UPLC BEHC₈ column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877)with a (2.1×5 mm, 1.7 μm particle) guard column (pn: 186003978), and adual gradient run from 2-98% mobile phase B over 4.45 minutes. Mobilephase A=H₂O (10 mM ammonium formate with 0.05% ammonium hydroxide).Mobile phase B=acetonitrile. Flow rate=0.6 mL/min, injection volume=2μL, and column temperature=45° C.

LC/MS Method F. LC/MS analysis was conducted using an Acquity UPLC BEHC₈ column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877)with a (2.1×5 mm, 1.7 μm particle) guard column (pn: 186003978), and adual gradient run from 2-98% mobile phase B over 1.5 minutes. Mobilephase A=H₂O (10 mM ammonium formate with 0.05% ammonium hydroxide).Mobile phase B=acetonitrile. Flow rate=0.6 mL/min, injection volume=2μL, and column temperature=45° C.

LC/MS Method G. LC/MS analysis was conducted using a Shimadzu 10-A LCsystem by reverse phase HPLC using an Onyx Monolithic C₁₈ column (50×4.6mm) made by Phenomenex (pn:CH0-7644), and a dual gradient run from5-100% mobile phase B over 4.2 minutes. Mobile phase A=H₂O (0.1%CF₃CO₂H). Mobile phase B═CH₃CN (0.1% CF₃CO₂H). Flow rate=1.5 mL/min,injection volume 10 μL and with the column at ambient temperature.

LC/MS Method H. LC/MS analysis was conducted using a Shimadzu 10-A LCsystem by reverse phase HPLC using an Onyx Monolithic C18 column (50×4.6mm) made by Phenomenex (pn:CH0-7644), and a dual gradient run from5-100% mobile phase B over 12 minutes. Mobile phase A=H₂O (0.1%CF₃CO₂H). Mobile phase B═CH₃CN (0.1% CF₃CO₂H). Flow rate=1.5 mL/min,injection volume 10 μL and with the column at ambient temperature.

LC/MS Method I. LC/MS analysis was conducted using an Acquity UPLC HSST3 C₈ column (50×2.1 mm, 1.8 μm particle) made by Waters (pn:186003538), and a dual gradient run from 1-99% mobile phase B over 2.90minutes. Mobile phase A=H₂O (10 mM ammonium formate). Mobile phaseB=acetonitrile. Flow rate=1.2 mL/min, injection volume=1.5 μL, andcolumn temperature=60° C.

Unless otherwise noted, where purification by reverse phase HPLC isindicated in the Examples below, samples were purified using a reversephase HPLC-MS method using a Luna C₁₈ (2) column (75×30 mm, 5 μmparticle size) sold by Phenomenex (pn: 00C-4252-U0-AX), and a dualgradient run from 1-99% mobile phase B over 15.0 minutes. Mobile phaseA=H₂O (5 mM HCl). Mobile phase B═CH₃CN. Flow rate=50 mL/min, injectionvolume=950 μL, and column temperature=25° C.

Abbreviations

Unless otherwise noted, or where the context dictates otherwise, thefollowing abbreviations shall be understood to have the followingmeanings:

Abbreviation Meaning NMR Nuclear magnetic resonance ESI-MS Electrospraymass spectrometry LC/MS Liquid chromatograph-mass spectrometry UPLCUltra performance liquid chromatography HPLC/MS/MS High performanceliquid chromatography/tandem mass spectrometry IS Internal standard HPLCHigh performance liquid chromatography SFC Supercritical fluidchromatography ESI Electrospray ionization g grams mg milligrams LLiter(s) mL Milliliters μL Microliters nL nanoliters mmol millimoles hr,h hours min Minutes ms millisecond mm Millimeters μm Micrometers nmnanometer MHz Megahertz Hz Hertz N Normal (concentration) M Molar(concentration) mM Millimolar (concentration) μM Micromolar(concentration) ppm Parts per million % w/v Weight-volume concentrationt-BuOH tert-butyl alcohol DCM Dichloromethane DIEA, DIPEAN,N-Diisopropyl ethyl amine DMA N,N-Dimethylacetamide DMFN,N-Dimethylformamide DMSO Dimethyl sulfoxide EtOH Ethanol HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate EDCI1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide T3P Propylphosphonicanhydride, i.e., 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide MeOH Methanol MTBE Methyl tert-butyl ether NMPN-Methylpyrrolidone THF Tetrahydrofuran TEA triethylamine RB Roundbottom (flask) RT Room temperature ca. Circa (approximately) E-VIPRElectrical stimulation voltage ion probe reader HEK Human embryonickidney KIR2.1 Inward-rectifier potassium ion channel 2.1 DMEM Dulbecco'sModified Eagle's Medium FBS Fetal bovine serum NEAA Non-essential aminoacids HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acidDiSBAC₆(3) Bis-(1,3-dihexyl-thiobarbituric acid) trimethine oxonolCC2-DMPE Chlorocoumarin-2-dimyristoyl phosphatidylethanolamine VABSC-1Voltage Assay Background Suppression Compound HS Human serum BSA BovineSerum Albumin

Preparation 14-[(Z)-[(tert-Butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide

A flask equipped with a reflux condenser was charged with4-aminopyridine-2-carboxamide (1.12 g, 8.17 mmol),benzenesulfonylsulfanylbenzene (1.85 g, 7.39 mmol),2-isocyano-2-methyl-propane (3.0 mL, 27 mmol), copper (I) iodide (60 mg,0.32 mmol) and molecular sieves (2.2 g) in 2-methyltetrahydrofuran (10mL), and the mixture was heated at 75° C. for 24 hours. The reactionmixture was filtered through Celite and the cake was rinsed with ethylacetate. The filtrate was concentrated and dried under vacuum. Theresidue was purified by silica gel chromatography (0-60% ethylacetate/hexanes) to obtain4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(1.25 g, 51%). ESI-MS m/z calc. 328.14, found 329.2 (M+1)+; retentiontime (Method B): 1.07 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 8.17 (dd, J=5.3, 0.6 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 7.49 (s, 1H),7.28 (dd, J=2.2, 0.6 Hz, 1H), 7.25-7.17 (m, 5H), 6.74 (dd, J=5.3, 2.2Hz, 1H), 6.66 (s, 1H), 1.35 (s, 9H) ppm.

Preparation 2 Methyl4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]-5-fluoro-pyridine-2-carboxylate

Methyl 4-amino-5-fluoro-pyridine-2-carboxylate (105 mg, 0.617 mmol),2-isocyano-2-methyl-propane (154 mg, 1.85 mmol),benzenesulfonylsulfanylbenzene (158 mg, 0.631 mmol) and copper (I)iodide (3.0 mg, 0.016 mmol) and 4 A molecular sieves (300 mg/mmol) in2-methyltetrahydrofuran (1.5 mL) were heated in a sealed vial at 75° C.for 24 hours. The mixture was filtered through Celite, washed with ethylacetate and concentrated in vacuo. Purification by silica gelchromatography (0-100% ethyl acetate/petroleum ether) afforded methyl4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]-5-fluoro-pyridine-2-carboxylateas a yellow oil (84 mg, 37%). ESI-MS m/z calc. 361.13, found 362.22(M+1)+; retention time (Method F): 1.01 minutes. ¹H NMR (500 MHz, CDCl₃)δ 8.34 (d, J=2.1 Hz, 1H), 7.73 (d, J=6.8 Hz, 1H), 7.46-7.42 (m, 2H),7.41-7.32 (m, 3H), 3.98 (s, 3H), 1.33 (s, 9H) ppm.

Preparation 3 4-Amino-6-methyl-pyridine-2-carboxamide

Step 1: Ethyl4-(tert-butoxycarbonylamino)-6-methyl-pyridine-2-carboxylate and methyl4-(tert-butoxycarbonylamino)-6-methyl-pyridine-2-carboxylate

A mixture of tert-butyl carbamate (352 mg, 3.01 mmol), ethyl4-chloro-6-methyl-pyridine-2-carboxylate (500 mg, 2.51 mmol),dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (120 mg,0.252 mmol), Cs₂CO₃ (1.15 g, 3.530 mmol) and Pd(OAc)₂ (18 mg, 0.08 mmol)in dioxane (20 mL) was heated at 100° C. for 16 hours. The reactionmixture was cooled to room temperature, filtered through Celite andrinsed with methanol. The filtrate was concentrated in vacuo to providethe desired product as a mixture of methyl and ethyl esters which weretaken directly to the next step. Methyl4-(tert-butoxycarbonylamino)-6-methyl-pyridine-2-carboxylate (333 mg).ESI-MS m/z calc. 266.13, found 267.1 (M+1)+; 265.0 (M−1)−; retentiontime (Method F): 0.77 minutes (1.5 minute run). Ethyl4-(tert-butoxycarbonylamino)-6-methyl-pyridine-2-carboxylate (351 mg).ESI-MS m/z calc. 280.14, found 281.1 (M+1)+; 279.0 (M−1)−; retentiontime (Method F): 0.83 minutes (1.5 minute run).

Step 2: tert-Butyl N-(2-carbamoyl-6-methyl-4-pyridyl)carbamate

A solution of ammonia (16 mL of 7 M in methanol, 112 mmol) was added toa mixture of ethyl4-(tert-butoxycarbonylamino)-6-methyl-pyridine-2-carboxylate (315 mg,1.12 mmol) and methyl4-(tert-butoxycarbonylamino)-6-methyl-pyridine-2-carboxylate (300 mg,1.13 mmol) and the resulting mixture was stirred at room temperature for3 days. The reaction mixture was concentrated in vacuo to providetert-butyl N-(2-carbamoyl-6-methyl-4-pyridyl)carbamate (560 mg, 99%) asa creamy solid. ESI-MS m/z calc. 251.13, found 252.1 (M+1)+; 250.0(M−1)−; retention time (Method F): 0.73 minutes (1.5 minute run).

Step 3: 4-Amino-6-methyl-pyridine-2-carboxamide

Trifluoroacetic acid (200 μL, 2.60 mmol) was added to a solution oftert-butyl N-(2-carbamoyl-6-methyl-4-pyridyl)carbamate (65 mg, 0.26mmol) in dichloromethane (5 mL) and the mixture was stirred for 16hours. The reaction mixture was concentrated in vacuo and the residuewas dissolved in dichloromethane and passed through a bicarbonate filtercartridge flushing with additional dichloromethane and methanol. Thecombined fractions were concentrated to provide4-amino-6-methyl-pyridine-2-carboxamide (38 mg, 97%) as a pale yellowoil that solidified on standing. ESI-MS m/z calc. 151.07, found 152.0(M+1)+; retention time (Method F): 0.36 minutes (1.5 minute run).

Preparation 4 5-Amino-2-fluoro-4-methyl-benzamide

To a solution of methyl 5-amino-2-fluoro-4-methyl-benzoate (500 mg, 2.73mmol) in methanol (3 mL) was added ammonia (2 mL of 7 M, 14 mmol), andthe mixture was stirred for 16 hours at room temperature. Additionalammonia (2 mL of 7 M, 14 mmol) was added and the reaction was stirredfor 6 hours. The reaction mixture was concentrated in vacuo to afford5-amino-2-fluoro-4-methyl-benzamide (390 mg, 85%) as a yellow solid.ESI-MS m/z calc. 168.07, found 169.0 (M+1)+; retention time (Method F):0.42 minutes (1.5 minute run).

Preparation 5 5-Amino-4-deuterio-2-fluoro-benzamide Step 1:4-chloro-2-fluoro-5-nitro-benzamide

To a solution of 4-chloro-2-fluoro-5-nitro-benzoic acid (4.00 g, 18.2mmol) and HATU (7.45 g, 19.6 mmol) in DMF (40 mL) was added a solutionof ammonia (60 mL of 0.5 M in dioxane, 30 mmol) dropwise and thereaction mixture was stirred at room temperature for 20 hours. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was extracted with 1 M NaOH to remove anyunreacted acid. The organic layer was then washed with brine, dried overMgSO₄, filtered and concentrated in vacuo. The solid was dissolved inwarm dichloromethane and the solution was allowed to cool to roomtemperature. The resulting crystals were filtered, washed with minimaldichloromethane and air dried to provide the desired product (0.73 g).The mother liquor was purified using silica gel chromatography (0-10%methanol/dichloromethane) to provide an additional 0.37 g of4-chloro-2-fluoro-5-nitro-benzamide (combined yield 1.100 g, 28%) as awhite solid. ESI-MS m/z calc. 217.99, found 219.1 (M+1)+; retention time(Method A): 0.39 minutes (1 minute run). ¹H NMR (400 MHz, DMSO-d6) δ8.37 (d, J=6.7 Hz, 1H), 8.00 (br s, 1H), 7.98 (d, J=9.7 Hz, 1H), 7.96(br s, 1H) ppm.

Step 2: 5-Amino-4-deuterio-2-fluoro-benzamide

A flask charged with 4-chloro-2-fluoro-5-nitro-benzamide (1.63 g, 7.46mmol) and dry 10% Pd/C (800 mg, 0.752 mmol) was put under high vacuumfor 1 hour then backfilled with N2. Methanol-d4 (20 mL) andtriethylamine (1.25 mL, 8.97 mmol) were added under N₂ atmosphere. Theflask was fixed with a deuterium balloon and stirred vigorously at roomtemperature, then cooled to 0° C. due to a rapid exotherm. The flask wasremoved from the ice bath after 10 minutes and allowed to warm to roomtemperature over 1 hour with continued stirring. The reaction mixturewas filtered through Celite and rinsed with methanol-d4. The filtratewas again filtered (0.45 micron syringe filter) and concentrated invacuo. Silica gel chromatography (5-10% methanol/dichloromethane)provided 5-amino-4-deuterio-2-fluoro-benzamide (845 mg, 73%) as a whitesolid. ESI-MS m/z calc. 155.06, found 156.1 (M+1)+; retention time(Method I): 0.52 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ7.44 (d, J=9.7 Hz, 2H), 6.90 (d, J=10.6 Hz, 1H), 6.83 (d, J=6.1 Hz, 1H),5.09 (s, 2H) ppm.

Example 1N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(1)

Step 1: 1-bromo-2-(trideuteriomethoxy)-4-(trifluoromethoxy)benzene

2-bromo-5-(trifluoromethoxy)phenol (57.5 g, 223.7 mmol) in DMF (400 mL)was treated with K₂CO₃ (62 g, 448.6 mmol), stirred for 15 minutes, andcooled in an ice bath, and iodomethane-d3 (Aldrich, >99.5% D, 15.3 mL,245.8 mmol) was added dropwise. The pale yellow suspension was removedfrom the ice bath and stirred at room temperature for 16 hours. Thesuspension was partitioned between water (2 L) and MTBE (500 mL) andseparated. The organic phase was washed with 0.5M NaOH (500 mL) andbrine (2×300 mL) and the aqueous phases were back extracted once withMTBE (250 ml). The combined organic phases were dried, filtered andevaporated to give1-bromo-2-(trideuteriomethoxy)-4-(trifluoromethoxy)benzene (62.4 g, 97%)as a pale yellow liquid. LC/MS retention time (Method B): 1.84 minutes(3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J=8.7 Hz, 1H), 7.14(d, J=2.6 Hz, 1H), 6.92 (ddq, J=8.7, 2.5, 1.3 Hz, 1H) ppm.

Step 2: 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol

A 1000 mL 3 neck RB flask was fitted with a mechanical stirrer, aheating mantle, a water cooled reflux condenser, temperatureprobe/controller and a nitrogen inlet/outlet was charged under anitrogen atmosphere with tetrabutylammonium hydroxide (354.8 mL of 55%w/w, 729.5 mmol) and1-bromo-2-(trideuteriomethoxy)-4-(trifluoromethoxy)benzene (50 g, 182.4mmol). With stirring, the solution was degassed with nitrogen for 15minutes. 1,10-phenanthroline-4,7-diol (3.871 g, 18.24 mmol) was thenadded as a solid in one portion followed by copper (I) oxide (1.305 g,9.120 mmol) added as a solid in one portion. After these additions, thegas dispersion tube was removed and the vessel was fitted with a septum.The resulting mixture was then heated to a pot temperature of 100° C.for 15 hours. After cooling to RT, the reaction mixture was poured intoice cold hydrochloric acid (912 mL of 1 M, 912.0 mmol). The mixture wasdiluted with ethyl acetate (500 ml) and mixed for several minutes. Thephases were separated and the aqueous phase was extracted with ethylacetate (2×200 mL). The combined organic phases were washed with brine(2×250 mL), dried over sodium sulfate (200 g), filtered andconcentrated. The residue was purified by silica gel chromatography(ethyl acetate/hexane gradient) to provide2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (33 g, 86%) as a clearpale yellow oil. LC/MS retention time (Method B): 1.38 minutes (3 minuterun). ¹H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 6.91 (dd, J=2.8, 0.9 Hz,1H), 6.82 (d, J=8.6 Hz, 1H), 6.79-6.70 (m, 1H) ppm.

Step 3:2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicAcid

A pressure bottle was charged with2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (2 g, 9.472 mmol),cesium carbonate (6.50 g, 19.94 mmol) and6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.81 g, 9.97 mmol) intoluene (71 mL). The mixture was degassed with nitrogen. After ca. 2minutes, copper (I) iodide (380 mg, 1.99 mmol) was added, the bottle wassealed, and the reaction was stirred at 110° C. for 40 minutes. Aftercooling to RT, the reaction was diluted with ethyl acetate and water.The organic phase was washed with brine and dried over sodium sulfate.Trituration with hexane and filtration gave2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (2.8 g, 67%). ESI-MS m/z calc. 417.05, found 418.1 (M+1)+;retention time (Method A): 0.73 minutes (1.2 minute run). ¹H NMR (400MHz, DMSO-d6) δ 7.35 (t, J=8.5 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.13 (d,J=8.7 Hz, 1H), 6.97 (ddt, J=8.8, 2.7, 1.2 Hz, 1H), 6.39 (d, J=8.6 Hz,1H) ppm.

Step 4:2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride

To a solution of2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (600 mg, 1.44 mmol) and DMF (20 μL, 0.26 mmol) in DCM (6.5 mL) at0° C. was added oxalyl chloride (800 μL, 9.17 mmol) dropwise. The icebath was removed and the reaction was stirred under N₂ atmosphere for 45minutes. The solvent was evaporated under reduced pressure to afford2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride. The intermediate was used in the next step without furtherpurification.

Step 5:N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(1)

To 5-amino-2-fluoro-benzamide (212 mg, 1.38 mmol) anddiisopropylethylamine (719 μL, 4.13 mmol) in dichloromethane (6 mL)cooled at 0° C. was added dropwise a solution of2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (600 mg, 1.377 mmol) in THF (6 mL). The reaction was stirred atroom temperature overnight. The mixture was concentrated and the residuewas purified by silica gel chromatography (ethyl acetate/hexanegradient) to provideN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(329 mg, 42%). ESI-MS m/z calc. 553.0963, found 554.1 (M+1)+; Retentiontime (Method B): 1.83 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.02 (s, 1H), 8.00 (dd, J=6.4, 2.8 Hz, 1H), 7.84-7.73 (m, 3H), 7.70(s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.33-7.26 (m, 2H), 7.05 (ddd, J=8.8,2.7, 1.3 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H) ppm.

The compounds set forth in Table 2 were prepared by methods analogous tothe preparation of compound 1.

TABLE 2 Additional Compounds Prepared By Methods Analogous to Example 1Cmpd No Compound Name LC/MS NMR (shifts in ppm) 127N-(4-carbamoylphenyl)-2- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-fluoro-6-[2- 535.09, found 535.9 d6) δ 11.08 (s, 1H), 7.93 (s,(trideuteriomethoxy)-4- (M + 1)+; Retention 1H), 7.92-7.8 7 (m, 2H),7.79 (trifluoromethoxy)phenoxy]-3- time (Method B): (t, J = 8.7 Hz, 1H),7.74 (d, J = (trifluoromethyl)benzamide 2.48 minutes (3 8.8 Hz, 2H),7.36 (d, J = 8.8 minute run). Hz, 1H), 7.32 (s, 1H), 7.27 (d, J = 2.8Hz, 1H), 7.05 (ddd, J = 8.8, 2.7, 1.3 Hz, 1H), 6.65 (d, J = 8.9 Hz, 1H)145 N-(3-carbamoyl-4-methyl- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-phenyl)-2-fluoro-6-[2- 549.12, found 551.0 d6) δ 10.84 (s, 1H), 7.78 (d,J = (trideuteriomethoxy)-4- (M + 1)+; Retention 8.7 Hz, 1H), 7.74 (d, J= 4.0 (trifluoromethoxy)phenoxy]-3- time (Method C): Hz, 1H), 7.69 (d, J= 2.3 Hz, (trifluoromethyl)benzamide 2.53 minutes (5 1H), 7.61 (dd, J =8.3, 2.3 Hz, minute run). 1H), 7.37 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H),7.26 (d, J = 2.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.08-7.02 (m, 1H),6.63 (d, J = 8.9 Hz, 1H), 2.31 (s, 3H). 209 5-[[2-fluoro-6-[2- ESI-MSm/z calc. ¹H NMR (400 MHz, DMSO- (trideuteriomethoxy)-4- 550.12, found551.0 d6) δ 11.35 (s, 1H), 8.89 (d, J = (trifluoromethoxy)phenoxy]-3-(M + 1)+; Retention 2.4 Hz, 1H), 8.73-8.57 (m,(trifluoromethyl)benzoyl]amino]- time (Method B): 1H), 8.28 (dd, J =8.6, 2.5 Hz, N-methyl-pyridine-2- 2.60 minutes (3 1H), 8.05 (d, J = 8.5Hz, 1H), carboxamide minute run). 7.81 (t, J = 8.7 Hz, 1H), 7.36 (d, J =8.7 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.68(d, J = 8.9 Hz, 1H), 2.81 (d, J = 4.8 Hz, 3H).

Example 2N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(2)

Step 1: 1-bromo-2-methoxy-4-(trifluoromethoxy)benzene

A 500 mL 3 neck RB flask was fitted with a mechanical stirrer, a coolingbath, an addition funnel, temperature probe and a nitrogen inlet/outlet.The vessel was charged under a nitrogen atmosphere with2-bromo-5-(trifluoromethoxy)phenol (80 g, 311.3 mmol),N,N-dimethylformamide (800 mL) and was treated with K₂CO₃ (56.05 g,405.6 mmol). The mixture was stirred at RT for 15 minutes and thencooled in an ice bath and methyl iodide (19.38 mL, 311.3 mmol) was addeddropwise over 5 minutes. The cooling bath was removed and the resultingsuspension was allowed to slowly warm to RT and continue to stir at RTfor 10 hours. The reaction mixture was then poured into crushedice/water (1000 mL) and stirred for 5 minutes. The mixture was dilutedwith methyl tert-butyl ether (1000 mL) and transferred to a separatoryfunnel and allowed to stand for 10 minutes. The organic phase wasseparated and the aqueous was extracted with methyl tert-butyl ether(2×500 ml). The combined organic phases were washed with brine, driedover sodium sulfate (500 g), filtered and concentrated. The crudeproduct was purified by silica gel chromatography (starting with hexane,then 9:1 hexane:dichloromethane and finally 8:1:1hexane:dichloromethane:ethyl acetate) to give1-bromo-2-methoxy-4-(trifluoromethoxy)benzene (82 g, 97%) as a paleyellow oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J=8.7 Hz, 1H),7.25-7.06 (m, 1H), 6.93 (ddq, J=8.7, 2.5, 1.2 Hz, 1H), 3.89 (s, 3H) ppm.

Step 2: 2-methoxy-4-(trifluoromethoxy)phenol

A 1000 mL 3 neck RB flask was fitted with a mechanical stirrer, aheating mantle, a water cooled reflux condenser, a temperatureprobe/controller and a nitrogen inlet/outlet. The vessel was chargedunder a nitrogen atmosphere with tetrabutylammonium hydroxide (287.2 mLof 40% w/v, 442.7 mmol) in water and1-bromo-2-methoxy-4-(trifluoromethoxy)benzene (30 g, 110.7 mmol). Withstirring the solution was degassed with nitrogen for 15 minutes. Thevessel was then charged with 1,10-phenanthroline-4,7-diol (2.349 g,11.07 mmol) added as a solid in one portion followed by copper (I) oxide(792 mg, 5.54 mmol) added as a solid in one portion. After theseadditions the gas dispersion tube was removed and the vessel was fittedwith a septum. The mixture was then heated to a pot temperature of 100°C. for 15 hours. After cooling to RT the reaction mixture was pouredinto ice cold hydrochloric acid (553.5 mL of 1 M, 553.5 mmol). Themixture was diluted with ethyl acetate (500 mL) and mixed for severalminutes. The biphasic mixture was transferred to a separatory funnel andallowed to stand for 5 minutes. The phases were separated and theaqueous was extracted with ethyl acetate (2×200 mL). The combinedorganic phases were washed with saturated brine (2×250 mL), dried oversodium sulfate, filtered and concentrated. The residue was purified bysilica gel chromatography (ethyl acetate/hexane gradient) to provide2-methoxy-4-(trifluoromethoxy)phenol (18 g, 78%) as a pale yellow oil.LC/MS retention time (Method B): 1.34 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 9.35 (s, 1H), 6.92 (dd, J=2.7, 0.8 Hz, 1H), 6.82(d, J=8.6 Hz, 1H), 6.79-6.70 (m, 1H), 3.79 (s, 3H) ppm.

Step 3:2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid

A pressure flask was charged with6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5 g, 17.42 mmol),2-methoxy-4-(trifluoromethoxy)phenol (4.35 g, 20.90 mmol), cesiumcarbonate (11.35 g, 34.84 mmol) and toluene (50 mL). The mixture wasdegassed with nitrogen. After ca. 2 minutes, copper (I) iodide (663 mg,3.48 mmol) was added and the reaction was stirred at 100° C. for 1 hr.The reaction was diluted with 300 mL ethyl acetate and 200 mL of waterand the phases were separated. The aqueous layer was acidified to pH-3and extracted with ethyl acetate. The combined organic phases were driedover sodium sulfate, filtered and concentrated. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane gradient, followed by9:1 dichloromethane:methanol) to afford2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (5.4503 g, 76%) as a pale green solid. ESI-MS m/z calc. 414.03,found 415.0 (M+1)+; retention time (Method B): 1.94 minutes (3 minuterun). ¹H NMR (400 MHz, DMSO-d6) δ 7.53 (t, J=8.4 Hz, 1H), 7.27-7.11 (m,2H), 6.99 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 3.80(s, 3H) ppm.

Step 4:2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride

To a slurry of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (660 mg, 1.59 mmol) and N,N-dimethylformamide (10 μL, 0.13 mmol) indichloromethane (6.5 mL) at 0° C. was added oxalyl chloride (550 μL,6.30 mmol) dropwise. The mixture was stirred at 50° C. for 40 minutesunder N₂ atmosphere. The solvent was evaporated under reduced pressureto afford2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride which was used in the next step without further purification.

Step 5:N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(2)

To a solution of 5-amino-2-fluoro-benzamide (111 mg, 0.724 mmol) andDIEA (378 μL, 2.17 mmol) in dichloromethane (2 mL) at 0° C. was added asolution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (313 mg, 0.723 mmol) in dichloromethane (2 mL) slowly, and thereaction was stirred at room temperature for 2 hours. The solvent wasevaporated by blowing down with nitrogen. The crude product wasdissolved in DMSO, filtered and purified by reverse phase HPLC to yieldN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(234 mg, 59%). ESI-MS m/z calc. 550.0775, found 551.0 (M+1)+; retentiontime (Method C): 2.56 minutes (5 minute run).

The compounds set forth in Table 3 were prepared by methods analogous tothe preparation of compound 2.

TABLE 3 Additional Compounds Prepared By Methods Analogous to Example 2Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 992-fluoro-N-[4-fluoro-3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6)(methylcarbamoyl)phenyl]-6-[2- calc. 564.09, δ 11.03 (s, 1H), 8.34-8.24(m, methoxy-4- found 565.0 1H), 7.98 (dd, J = 6.3, 2.8 Hz,(trifluoromethoxy)phenoxy]-3- (M + 1)+; 1H), 7.84-7.68 (m, 2H), 7.37-(trifluoromethyl)benzamide Retention time 7.26 (m, 3H), 7.14-6.97 (m,(Method C): 1H), 6.64 (d, J = 8.9 Hz, 1H), 2.67 minutes (5 3.79 (s, 3H),2.78 (d, J = 4.6 Hz, minute run). 3H). 44N-(3-carbamoylphenyl)-2-fluoro- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6)6-[2-methoxy-4- calc. 532.09, δ 10.98 (s, 1H), 8.17 (t, J = 1.9(trifluoromethoxy)phenoxy]-3- found 533.1 Hz, 1H), 8. 00 (s, 1H), 7.82(ddd, (trifluoromethyl)benzamide (M + 1)+; J = 8.2, 2.3, 1.1 Hz, 1H),7.77 (d, Retention time J = 8.7 Hz, 1H), 7.62 (dt, J = 7.7, (Method B):1.2 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1.73 minutes (3 1H), 7.39 (s, 1H),7.36 (d, J = 8.8 minute run). Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.05(ddd, J = 8.8, 2.7, 1.3 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 3.80 (s, 3H)100 N-(3-carbamoyl-5-fluoro-phenyl)- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d6) 2-fluoro-6-[2-methoxy-4- calc. 550.08, δ 11.22 (s, 1H), 8.07(s, 1H), 7.93 (trifluoromethoxy)phenoxy]-3- found 551.1 (t, J = 1.6 Hz,1H), 7.83-7.76 (trifluoromethyl)benzamide (M + 1)+; (m, 2H), 7.55 (s,1H), 7.47 (ddd, Retention time J = 9.3, 2.4, 1.4 Hz, 1H), 7.37 (d,(Method B): J = 8.8 Hz, 1H), 7.28 (dd, J = 6.1, 1.85 minutes (3 2.7 Hz,1H), 7.05 (ddq, J = 7.6, minute run). 2.4, 1.2 Hz, 1H), 6.66 (d, J = 8.9Hz, 1H), 3.79 (s, 3H). 52 5-[[2-fluoro-6-[2-methoxy-4- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d6) (trifluoromethoxy)phenoxy]-3- calc. 533.08, δ 11.27(s, 1H), 8.91 (d, J = 2.4 (trifluoromethyl)benzoyl]ami- found 534.0 Hz,1H), 8.80 (d, J = 2.0 Hz, 1H), no]pyridine-3-carboxamide (M + 1)+; 8.57(t, J = 2.2 Hz, 1H), 8.22 (s, Retention time 1H), 7.80 (t, J = 8.6 Hz,1H), 7.64 (Method B): (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 1.63 minutes (37.27 (d, J = 2.7 Hz, 1H), 7.08- minute run). 7.00 (m, 1H), 6.67 (d, J =8.9 Hz, 1H), 3.80 (s, 3H). 98 2-fluoro-6-[2-methoxy-4- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d6) (trifluoromethoxy)phenoxy]-N-[3- calc. 546.10, δ10.99 (s, 1H), 8.51-8.40 (m, (methylcarbamoyl)phenyl]-3- found 546.91H), 8.16 (t, J = 1.9 Hz, 1H), 7.86- (trifluoromethyl)benzamide (M +1)+; 7.72 (m, 2H), 7.61-7.51 (m, Retention time 1H), 7.44 (t, J = 7.9Hz, 1H), 7.36 (Method C): (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.59 minutes(5 2.8 Hz, 1H), 7.10-6.99 (m, 1H), minute run). 6.64 (d, J = 8.8 Hz,1H), 3.79 (s, 3H), 2.78 (d, J = 4.5 Hz, 3H). 1935-[[2-fluoro-6-[2-methoxy-4- ESI-MS m/z ¹H NMR (500 MHz, DMSO-d6)(trifluoromethoxy)phenoxy]-3- calc. 533.08, δ 11.35 (s, 1H), 8.87 (d, J= 2.4 (trifluoromethyl)benzoyl]ami- found 534.0 Hz, 1H), 8.30 (dd, J =8.5, 2.5 no]pyridine-2-carboxamide (M + 1)+; Hz, 1H), 8.10-8.00 (m, 2H),Retention time 7.82 (t, J = 8.6 Hz, 1H), 7.56 (s, (Method E): 1H), 7.37(d, J = 8.8 Hz, 1H), 3.25 minutes (5 7.27 (d, J = 2.7 Hz, 1H), 7.08-minute run). 7.02 (m, 1H), 6.69 (d, J = 8.9 Hz, 1H), 3.79 (s, 3H). 974-[[2-fluoro-6-[2-methoxy-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6)(trifluoromethoxy)phenoxy]-3- calc. 561.11, δ 11.43 (s, 1H), 8.51 (d, J= 5.5 (trifluoromethyl)benzoyl]amino]- found 562.0 Hz, 1H), 7.86-7.78(m, 2H), 7.67 N,N-dimethyl-pyridine-2- (M + 1)+; (dd, J = 5.6, 2.2 Hz,1H), 7.37 (d, carboxamide Retention time J = 8.8 Hz, 1H), 7.27 (d, J =2.7 (Method C): Hz, 1H), 7.05 (ddd, J = 8.8, 2.7, 2.47 minutes (5 1.3Hz, 1H), 6.67 (d, J = 8.9 Hz, minute run). 1H), 3.79 (s, 3H), 3.00 (s,3H), 2.95 (s, 3H). 86 4-[[2-fluoro-6-[2-methoxy-4- ESI-MS m/z ¹H NMR(500 MHz, DMSO-d6) (trifluoromethoxy)phenoxy]-3- calc. 547.10, δ11.37-11.31 (m, 1H), 8.13- (trifluoromethyl)benzoyl]amino]- found 548.08.09 (m, 1H), 7.97 (d, J = 3.1 Hz, 6-methyl-pyridine-2-carboxamide (M +1)+; 1H), 7.81 (t, J = 8.6 Hz, 1H), 7.74 Retention time (d, J = 1.9 Hz,1H), 7.62 (d, J = (Method E): 3.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 3.37minutes (5 1H), 7.26 (d, J = 2.7 Hz, 1H), minute run). 7.05 (ddt, J =8.8, 2.3, 1.2 Hz, 1H), 6.71-6.65 (m, 1H), 3.79 (s, 3H), 3.29 (s, 3H). 95N-[3-(dimethylcarbamoyl)-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6)fluoro-phenyl]-2-fluoro-6-[2- calc. 578.11, δ 11.05 (s, 1H), 7.82-7.74(m, methoxy-4- found 578.9 2H), 7.69 (ddd, J = 9.0, 4.7, 2.7(trifluoromethoxy)phenoxy]-3- (M + 1)+; Hz, 1H), 7.38-7.29 (m, 2H),(trifluoromethyl)benzamide Retention time 7.27 (d, J = 2.8 Hz, 1H),7.11- (Method B): 7.02 (m, 1H), 6.65 (d, J = 8.9 Hz, 1.93 minutes (31H), 3.79 (s, 3H), 3.00 (s, 3H), minute run). 2.87 (d, J = 1.3 Hz, 3H).96 N-[3-(dimethy lcarbamoyl)phenyl]- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d6) 2-fluoro-6-[2-methoxy-4- calc. 560.12, δ 10.99 (s, 1H),7.82-7.75 (m, (trifluoromethoxy)phenoxy]-3- found 561.0 2H), 7.68 (ddd,J = 8.2, 2.2, 1.1 (trifluoromethyl)benzamide (M + 1)+; Hz, 1H), 7.43 (t,J = 7.9 Hz, 1H), Retention time 7.36 (d, J = 8.8 Hz, 1H), 7.27 (d,(Method C): J = 2.8 Hz, 1H), 7.16 (dt, J = 7.7, 2.69 minutes (5 1.3 Hz,1H), 7.05 (ddd, J = 8.8, minute run). 2.7, 1.3 Hz, 1H), 6.65 (d, J = 8.9Hz, 1H), 3.79 (s, 3H), 2.98 (s, 3H), 2.92 (s, 3H). 82N-(4-carbamoyl-2-fluoro-phenyl)- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6)2-fluoro-6-[2-methoxy-4- calc. 550.08, δ 10.9 1 (s, 1H), 8.13 (t, J =8.3 (trifluoromethoxy)phenoxy]-3- found 551.2 Hz, 1H), 8.04 (s, 1H),7.82-7.74 (trifluoromethyl)benzamide (M + 1)+; (m, 3H), 7.50 (s, 1H),7.36 (d, J = Retention time 8.8 Hz, 1H), 7.27 (d, J = 2.7 Hz, (MethodB): 1H), 7.06 (ddd, J = 8.8, 2.7, 1.3 1.81 minutes (3 Hz, 1H), 6.64 (d,J = 8.9 Hz, 1H), minute run). 3.80 (s, 3H). 118[N-(5-carbamoyl-4-fluoro-2- ESI-MS m/z ¹H NMR (500 MHz, DMSO-d6)methyl-phenyl)-2-fluoro-6-[2- calc. 564.09, δ 10.37 (s, 1H), 7.81-7.70(m, methoxy-4- found 565.2 2H), 7.63 (d, J = 13.7 Hz, 2H),(trifluoromethoxy)phenoxy]-3- (M + 1)+; 7.36 (d, J = 8.8 Hz, 1H), 7.31-(trifluoromethyl)benzamide Retention time 7.27 (m, 1H), 7.23 (d, J =11.3 (Method E): Hz, 1H), 7.07 (ddt, J = 8.7, 2.3, 3.41 minutes (5 1.2Hz, 1H), 6.65 (d, J = 8.9 Hz, minute run). 1H), 3.82 (s, 3H), 2.28 (s,3H). 87 2-[[2-fluoro-6-[2-methoxy-4- ESI-MS m/z ¹H NMR (500 MHz, DMSO-d6) (trifluoromethoxy)phenoxy]-3- calc. 533.08, δ 11.53 (s, 1H), 8.57 (s,1H), 8.49 (trifluoromethyl)benzoyl]ami- found 533.9 (d, J = 5.1 Hz, 1H),8.28 (d, J = no]pyridine-4-carboxamide (M + 1)+; 12.3 Hz, 1H), 7.81-7.70(m, Retention time 2H), 7.59-7.55 (m, 1H), 7.37 (d, (Method B): J = 8.8Hz, 1H), 7.26 (d, J = 2.8 1.75 minutes (3 Hz, 1H), 7.05 (d, J = 8.8 Hz,1H), minute run). 6.63 (d, J = 9.0 Hz, 1H), 3.80 (s, 3H)

Example 3N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide(3)

Step 1: 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic Acid

To a suspension of 6-bromo-2-fluoro-3-(trifluoromethoxy)benzaldehyde(2.8 g, 9.76 mmol) in t-butanol (15 mL), water (15 mL) and acetonitrile(15 mL) was added sodium dihydrogen phosphate (3.53 g, 29.42 mmol) and2-methyl-2-butene (5.6 mL, 52.94 mmol). Sodium chlorite (2.7 g, 29.85mmol) was added portion wise with cooling in an ice bath and an exothermand bubbling was observed during the addition. The reaction was removedfrom the ice bath and allowed to warm warmed to room temperature. After20 minutes the mixture was acidified with aqueous HCl (140 mL, 1 M,140.0 mmol) and diluted with ethyl acetate. The layers were separatedand the organic layer was washed with brine, dried over sodium sulfate,filtered and concentrated. Silica gel chromatography(dichloromethane/methanol gradient with 0.2% acetic acid) provided6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (2.10 g, 71%). ESI-MSm/z calc. 301.92, found 304.0 (M+1)+; retention time (Method A): 0.52minutes (1.2 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 14.52 (br s, 1H),7.78-7.56 (m, 2H) ppm.

Step 2:2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicAcid

To a pressure flask was added6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (600 mg, 1.98 mmol),2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (prepared as describedin Example 1, 420 mg, 1.99 mmol), cesium carbonate (1.29 g, 3.96 mmol),and toluene (15 mL). The reaction mixture was degassed with N2 for 10min, then copper (I) iodide (75 mg, 0.39 mmol) was added. The flask wasflushed with N2, capped, and heated at 100° C. with vigorous stirringfor 2 h. The mixture was allowed to cool to RT and was then diluted withethyl acetate and water. The water layer was acidified with 1M HCl andwas extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.Silica gel chromatography (dichloromethane/methanol gradient with 0.5%acetic acid) provided2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (672 mg, 78%). ESI-MS m/z calc. 433.05, found 434.2 (M+1)+;retention time (Method B): 1.83 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 14.02 (s, 1H), 7.56 (td, J=9.0, 1.2 Hz, 1H), 7.29-7.18 (m,2H), 7.00 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.58 (dd, J=9.3, 1.7 Hz, 1H)ppm.

Step 3:N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide(3)

2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (55 mg, 0.13 mmol) and HATU (49 mg, 0.13 mmol) were combined in DMF(1 mL) and DIEA (90 μL, 0.5167 mmol), stirred for 5 min, and thentreated with 5-amino-2-fluoro-benzamide (24 mg, 0.16 mmol). The reactionwas stirred at 45° C. for 30 min. Reverse phase HPLC purificationprovidedN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide(11.6 mg, 16%). ESI-MS m/z calc. 569.09, found 570.2 (M+1)+; retentiontime (Method B): 1.8 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ10.98 (s, 1H), 7.99 (dd, J=6.4, 2.8 Hz, 1H), 7.78 (ddd, J=9.0, 4.4, 2.8Hz, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.59 (t, J=9.0 Hz, 1H), 7.30 (dd,J=9.2, 1.7 Hz, 2H), 7.22 (d, J=2.8 Hz, 1H), 7.05-6.99 (m, 1H), 6.61 (dd,J=9.2, 1.6 Hz, 1H) ppm.

The compounds set forth in Table 4 were prepared by methods analogous tothe preparation of compound 3.

TABLE 4 Additional Compounds Prepared By Methods Analogous to Example 3Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 167 5-[[2-fluoro-6-[2-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ 11.33 (trideuteriomethoxy)-4-calc. 552.10, (s, 1H), 8.86 (dd, J = 2.5, 0.7 Hz, 1H),(trifluoromethoxy)phenoxy]- found 553.3 8.28 (dd, J = 8.6, 2.5 Hz, 1H),8.06 (dd, J = 3-(trifluoromethoxy)benzoyl]ami- (M + 1)+; 8.5, 0.7 Hz,1H), 8.02 (d, J = 2.3 Hz, no]pyridine-2-carboxamide Retention time 2H),7.63 (td, J = 9.1, 1.2 Hz, 1H), 7.57 (Method B): (d, J = 2.0 Hz, 1H),7.32 (d, J = 8.8 Hz, 1.77 minutes (3 1H), 7.22 (dd, J = 2.8, 0.8 Hz,1H), 7.02 minute run). (ddd, J = 8.8, 2.7, 1.2 Hz, 1H), 6.65 (dd, J =9.2, 1.6 Hz, 1H).

Example 44-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(4)

A microwave vial charged with4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(75 mg, 0.29 mmol, prepared as described in Preparation 1),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (approximately 2 mg, 0.0057mmol) and2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 2, 94 mg, 0.29 mmol) inisopropanol (2 mL) was heated at 83° C. for 16 hours. The reactionmixture was cooled to room temperature and the solvent evaporated. Thecrude material was taken up in dichloromethane and washed with 1N HCl.The organic layer was dried over MgSO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography (ethyl acetate/hexanegradient) to afford4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(80 mg, 64%). ESI-MS m/z calc. 533.08215, found 534.1 (M+1)+; retentiontime (Method B): 1.77 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.45 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.12(d, J=2.7 Hz, 1H), 7.86-7.77 (m, 2H), 7.72-7.64 (m, 1H), 7.38 (d, J=8.8Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 7.08-7.01 (m, 1H), 6.68 (d, J=8.9 Hz,1H), 3.79 (s, 3H) ppm.

Example 54-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(5)

Step 1: 6-bromo-3-chloro-2-fluoro-benzoic Acid

To a solution of 6-bromo-3-chloro-2-fluoro-benzaldehyde (1000 mg, 4.21mmol) in a mixture of t-BuOH (7 mL) and water (5 mL) was added sodiumdihydrogenphosphate (600 mg, 5.00 mmol) and 2-methyl-2-butene (9.5 mL of2 M, 19.00 mmol). NaClO₂ (600 mg, 5.31 mmol) was then added in 1portion. After 2 hours, the reaction mixture was acidified with 1M HCl,and extracted with ethyl acetate. The combined organic phases were driedover MgSO₄, filtered and concentrated under reduced pressure to afford6-bromo-3-chloro-2-fluoro-benzoic acid (900 mg, 84%), which was used inthe next step without further purification. ESI-MS m/z calc. 251.90,found 209.0 (M+1)+ (decarboxylated fragment); retention time (Method D):0.36 minutes (1.15 minute run).

Step 2:3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic Acid

To a mixture of 6-bromo-3-chloro-2-fluoro-benzoic acid (900 mg, 3.55mmol), 2-methoxy-4-(trifluoromethoxy)phenol (prepared as described inExample 2, 1 g, 4.80 mmol) and cesium carbonate (2.5 g, 7.67 mmol) intoluene (20 mL) was added copper (I) iodide (220 mg, 1.16 mmol). Theresulting mixture was heated at 100° C. for 4 hours. The mixture wascooled to RT, the pH was adjusted to ˜2 by addition of 2M HCl (aq) andthe mixture was then extracted with ethyl acetate (2×30 mL). The organicphases were combined, washed with water (20 mL), brine (2×20 mL), dried(phase separation cartridge) and concentrated to afford a yellow-orangesolid. The crude product was purified by reverse phase chromatography(ISCO 120 g C18 column, 0-100% CH₃CN:water-0.1% TFA gradient) to afford3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(680 mg, 50%) as a cream-colored solid. ESI-MS m/z calc. 380.01, found378.9 (M−1)−; retention time (Method D): 0.69 minutes (1.15 minute run).

Step 3: methyl 4-aminopyridine-2-carboxylate

To 4-aminopyridine-2-carboxylic acid (665 mg, 4.815 mmol) in methanol(25 mL) was added conc. sulfuric acid (257 μL, 4.82 mmol) and themixture was heated at reflux overnight. The mixture was cooled to RT andconcentrated under reduced pressure. The residue was diluted withsaturated NaHCO₃ and extracted with dichloromethane (2×) followed bychloroform (3×). The combined organic phases were dried (MgSO₄),filtered and evaporated to dryness to give methyl4-aminopyridine-2-carboxylate (370 mg, 51%) as a yellow solid. ESI-MSm/z calc. 151.06, found 152.85 (M+1)+; retention time (Method UK2): 1.55minutes (4.55 minute run).

Step 4: methyl4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(180 mg, 0.47 mmol) in dichloromethane (3 mL) was added DMF (3.9 μL,0.05 mmol), followed by dropwise addition of oxalyl chloride (141 μL,1.616 mmol). The mixture was warmed to room temperature over 3 hours.The reaction mixture was then concentrated, dissolved in dichloromethane(3 mL) and cooled in an ice bath. Methyl 4-aminopyridine-2-carboxylate(94 mg, 0.62 mmol) was added followed by TEA (253 μL, 1.82 mmol). Theresulting mixture was stirred and warmed to ambient temperature over 16hours. The reaction mixture was quenched with water (10 mL) andextracted with dichloromethane (2×10 mL). The combined organic phaseswere dried (MgSO₄), filtered and concentrated. The residue was purifiedby silica gel chromatography (ethyl acetate/petroleum ether gradient) togive methyl4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(200 mg, 82%). ESI-MS m/z calc. 514.0555, found 515.0 (M+1)+; retentiontime (Method D): 1.0 minutes (1.15 minute run).

Step 5:4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(5)

Methyl4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(200 mg, 0.3885 mmol) was stirred in aqueous ammonia (6.3 mL of 7 M,44.10 mmol) overnight. The reaction was concentrated and residue wastriturated from ethyl acetate and ether to give4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(173.3 mg, 88%). ESI-MS m/z calc. 499.05, found 500.0 (M+1)+; retentiontime (Method E): 3.3 minutes (4.45 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 11.36 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.2 Hz,1H), 8.11 (d, J=2.9 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.74-7.55 (m,1H), 7.39-7.12 (m, 2H), 7.00 (ddd, J=8.8, 2.7, 1.3 Hz, 2H), 6.64 (dd,J=9.0, 1.4 Hz, 1H), 3.78 (s, 3H) ppm.

Example 64-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(6)

To an ice cold solution of2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 1, 5 g, 11.98 mmol) and DMF (46μL, 0.5941 mmol) in anhydrous dichloromethane (50 mL) under nitrogen wasadded oxalyl chloride (1.7 mL, 19.49 mmol) dropwise. Five minutes afterthe addition the ice bath was removed and the mixture was stirred atroom temperature for 1 hour and at 35° C. for 15 min. The mixture wasconcentrated under reduced pressure and the residue was dissolved indichloromethane (12.5 mL) and the resulting solution was added dropwiseto a cold solution of 4-aminopyridine-2-carboxamide (1.97 g, 14.36 mmol)and DIEA (5.2 mL, 29.85 mmol) in NMP (50 mL) keeping the internaltemperature between 1 and 5° C. The mixture was stirred for 10 minutes,and then the ice bath was removed and the mixture was stirred at roomtemperature for 2 hours. The reaction was partitioned between water (250mL) and dichloromethane (50 mL) and the dichloromethane phase was washedwith water (250 mL) and brine (100 mL) and the combined aqueous phaseswere back extracted with dichloromethane (25 mL). The combined organicphases were dried, filtered and evaporated. The residue was purified bysilica gel chromatography (dichloromethane/methanol gradient) to give5.75 g of an oil which was dissolved in ethyl acetate (50 mL), washedthree times with water (3×50 mL) and once with brine (50 mL). Theaqueous phases were back extracted once with ethyl acetate (25 mL) andthe combined organic phases were dried, filtered, and concentrated underreduced pressure to give4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(3.7 g, 57%) as a cream colored foam. ESI-MS m/z calc. 536.10, found537.0 (M+1)+; retention time (Method B): 1.81 (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.33 (d,J=2.1 Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 7.88-7.77 (m, 2H), 7.66 (d, J=2.8Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 7.08-7.01 (m,1H), 6.68 (d, J=8.9 Hz, 1H) ppm.

Example 7N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(7)

Step 1: methyl3-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A vial charged with methyl 3-bromo-2,6-difluoro-benzoate (1 g, 3.98mmol), 2-methoxy-4-(trifluoromethoxy)phenol (prepared as described inExample 2, 830 mg, 3.988 mmol) and Cs₂CO₃ (2.5 g, 7.67 mmol) in DMF (20mL) was stirred at room temperature overnight. The reaction mixture wasquenched with water and the aqueous layer was extracted with ethylacetate. The organic phase was washed with brine, dried over MgSO₄,filtered and concentrated. The resulting residue was purified by silicagel chromatography (ethyl acetate/hexane gradient) to give methyl3-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (250mg, 14%). ESI-MS m/z calc. 439.97, found 440.9 (M+1)+; retention time(Method A): 0.83 minutes (1.2 minute run). ¹H NMR (400 MHz, DMSO-d6) δ7.73 (dd, J=9.0, 8.1 Hz, 1H), 7.27-7.23 (m, 2H), 7.00 (ddq, J=8.7, 2.4,1.1 Hz, 1H), 6.54 (dd, J=9.0, 1.4 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H)ppm.

Step 2: methyl2-fluoro-3-formyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A solution of methyl3-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (250mg, 0.57 mmol) in dry THF (2.5 mL) was purged with N2. The solution wascooled to −70° C., iPrMgCl (350 μL of 2 M in diethyl ether, 0.70 mmol),was added dropwise while maintaining the reaction temperature below −60°C. DMF (500 μL, 6.457 mmol) was added immediately after (maintain tempbelow −40° C.) and the reaction was stirred for 20 minutes at −70° C.and then warmed to 25° C. and allowed to stir for an additional 30minutes. The reaction was quenched with aqueous 1N HCl and extractedwith ethyl acetate. The organic phase was washed with brine, dried overmagnesium sulfate, filtered and concentrated. The resulting residue waspurified by silica gel chromatography (ethyl acetate/hexane gradient) togive methyl2-fluoro-3-formyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (135mg, 61%). ESI-MS m/z calc. 388.06, found 389.0 (M+1)+; retention time(Method A): 0.73 minutes (1.2 minute run). ¹H NMR (400 MHz, DMSO-d6) δ10.09 (s, 1H), 7.87 (dd, J=8.9, 8.1 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H),7.29 (d, J=2.8 Hz, 1H), 7.04 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.64 (d,J=8.8 Hz, 1H), 3.90 (s, 3H), 3.78 (s, 3H) ppm.

Step 3: methyl3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

Deoxo-Fluor® (Bis(2-methoxyethyl)aminosulfur trifluoride) (350 μL, 1.90mmol) was added to methyl2-fluoro-3-formyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (130mg, 0.33 mmol) followed by 2 drops of EtOH and the mixture was stirredat RT overnight. The mixture was cooled to 0° C. and quenched with sat.aqueous sodium bicarbonate (gas evolution) and then extracted with ethylacetate (3×). The combined organic phases were washed with water andbrine, dried (MgSO₄) and evaporated to dryness. The crude material wasagain treated with Deoxo-Fluor® (200 μL) and stirred for 2 hours. Themixture was cooled to 0° C. and quenched with sat. aqueous sodiumbicarbonate (gas evolution) and then extracted with ethyl acetate (3×).The combined organic phases were washed with water and brine, dried(MgSO₄) and evaporated to dryness. The residue was purified by silicagel chromatography (ethyl acetate/hexane gradient) to give methyl3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(90 mg, 66%). ESI-MS m/z calc. 410.06, found 411.0 (M+1)+; retentiontime (Method B): 2.01 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 7.66 (t, J=8.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.8 Hz,1H), 7.13 (t, J=54.2 Hz, 1H), 7.02 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.63(d, J=8.7 Hz, 1H), 3.88 (s, 3H), 3.78 (s, 3H) ppm.

Step 4:3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicAcid

To a flask charged with methyl3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(175 mg, 0.43 mmol) in MeOH (2 mL) was added NaOH (1.5 mL of 3M, 4.50mmol), and the mixture was stirred for 4 hours at room temperature. Thesolvent was evaporated, the reaction mixture was cooled to 0° C. andquenched with 6N HCl, and was extracted with dichloromethane. Theorganic layer was dried over MgSO₄, filtered and concentrated to obtain3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (150 mg, 89%). ESI-MS m/z calc. 396.04324, found 397.0 (M+1)+;retention time (Method B): 1.74 minutes (3 minute run).

Step 5:3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride

To a solution of3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (150 mg, 0.38 mmol) and DMF (10 μL, 0.13 mmol) in dichloromethane(2 mL) at 0° C. was added oxalyl chloride (50 μL, 0.5732 mmol) dropwise.The mixture was stirred at room temperature for 30 minutes. The solventwas evaporated under reduced pressure to afford3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride, which was used without purification in the next step.

Step 6:N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(7)

A solution of 5-amino-2-fluoro-benzamide (29 mg, 0.19 mmol) and DIEA(100 μL, 0.57 mmol) in THF (1 mL) was cooled to 0° C. To this solutionwas added a suspension of3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride (75 mg, 0.1809 mmol) in THF (1 mL) and dichloromethane (1 mL).The reaction mixture was gradually warmed to room temperature andstirred for 16 hours. The reaction mixture was quenched with water andthe aqueous layer was extracted with dichloromethane. The organic phasewas washed with 1N HCl (2×), dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(ethyl acetate/hexane gradient) to affordN-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(29 mg, 29%). ESI-MS m/z calc. 532.09, found 533.1 (M+1)+; retentiontime (Method B): 1.72 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.95 (s, 1H), 8.00 (dd, J=6.4, 2.8 Hz, 1H), 7.78 (ddd, J=8.9, 4.4,2.8 Hz, 1H), 7.73 (s, 1H), 7.65 (dd, J=17.3, 9.0 Hz, 2H), 7.34-7.23 (m,3H), 7.15 (t, J=54.2 Hz, 1H), 7.03 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.62(d, J=8.7 Hz, 1H), 3.79 (s, 3H) ppm.

Example 84-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(8)

A solution of2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (prepared as described in Example 3, 600 mg, 1.39 mmol) indichloromethane (12 mL) was cooled using an ice-bath. To this was addedDMF (20 μL, 0.26 mmol) followed by careful addition of oxalyl chloride(275 μL, 3.15 mmol). The solution was stirred for 10 minutes thenremoved from the ice bath and allowed to warm to room temperature over 1h. The reaction was concentrated under reduced pressure and azeotropedwith dichloromethane to afford 2,5-difluoro-4-(trifluoromethyl)benzoylchloride, which was used without purification. An ice cold solution ofthis material in dichloromethane (6 mL) was added to an ice coldsolution of 4-aminopyridine-2-carboxamide (190 mg, 1.39 mmol),dichloromethane (6 mL), NMP (2 mL) and DIEA (725 μL, 4.16 mmol). Thereaction was stirred for 10 minutes then removed from the ice bath andallowed to come to room temperature over 1 hour. The reaction wasconcentrated and purified by reverse phase HPLC to provide4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(316 mg, 41%). ESI-MS m/z calc. 552.10, found 553.2 (M+1)+; retentiontime (Method B): 1.77 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.41 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.10(d, J=2.8 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.69-7.58 (m, 2H), 7.32(d, J=8.8 Hz, 1H), 7.22 (dd, J=2.8, 0.8 Hz, 1H), 7.02 (ddd, J=8.8, 2.7,1.2 Hz, 1H), 6.65 (dd, J=9.2, 1.6 Hz, 1H) ppm.

Example 9N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide(9)

Step 1:6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicAcid

A pressure flask was charged with6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (3.24 g, 11.29 mmol),cesium carbonate (7.357 g, 22.58 mmol) and2-chloro-4-(trifluoromethoxy)phenol (2.4 g, 11.29 mmol) in toluene (24.3mL). The mixture was degassed with nitrogen. After ca. 2 minutes, copper(I) iodide (430 mg, 2.258 mmol) was added and the reaction was stirredat 100° C. for 10 minutes. The reaction was diluted with ethyl acetateand water. The phases were separated and the organic phase was washedwith brine and dried over sodium sulfate. Trituration with hexane (2×)and filtration gave6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (3.54 g, 75%). ESI-MS m/z calc. 417.98, found 419.2 (M+1)+;retention time (Method B): 1.9 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 7.74 (d, J=2.8 Hz, 1H), 7.46 (t, J=8.3 Hz, 1H), 7.42-7.34 (m,1H), 7.15 (d, J=9.0 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H) ppm.

Step 2:6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride

To6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (600 mg, 1.43 mmol) and N,N-dimethylformamide (10 μL, 0.13 mmol) indichloromethane (7 mL) at 0° C. was added oxalyl chloride (609 μL, 6.99mmol) dropwise. The mixture was stirred at room temperature for 15minutes under a N₂ atmosphere. The solvent was evaporated under reducedpressure to afford6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride (626 mg, 100%), which was used in the next step without furtherpurification.

Step 3:N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide(9)

To 5-amino-2-fluoro-benzamide (70.54 mg, 0.4576 mmol) anddiisopropylethylamine (178 mg, 1.37 mmol) in dichloromethane (2.4 mL)cooled at 0° C. was added dropwise a solution of6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride (200 mg, 0.46 mmol) in dichloromethane (2.4 mL). The reactionwas stirred at room temperature overnight. The crude material waspurified by silica gel chromatography (ethyl acetate/hexane gradient) toobtainN-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide(85 mg, 33%). ESI-MS m/z calc. 554.03, found 555.0 (M+1)+; retentiontime (Method B): 1.9 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.06 (s, 1H), 7.98 (dd, J=6.4, 2.8 Hz, 1H), 7.95-7.82 (m, 2H),7.80-7.59 (m, 3H), 7.52 (d, J=2.4 Hz, 2H), 7.30 (dd, J=10.0, 9.1 Hz,1H), 6.85 (d, J=8.8 Hz, 1H) ppm.

The compounds set forth in Table 5 were prepared by methods analogous tothe preparation of compound 9.

TABLE 5 Additional Compounds Prepared By Methods Analogous to Example 9Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 51 4-[[6-[2-chloro-4-ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δ(trifluoromethoxy)phenoxy]-2- 537.03 found 11.50 (s, 1H), 8.57 (d, J =5.5 Hz, fluoro-3- 538.0 (M + 1)+; 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.12(trifluoromethyl)benzoyl]amino] Retention time (d, J = 2.7 Hz, 1H),7.94-7.77 (m, pyridine-2-carboxamide (Method B): 1.84 3H), 7.68 (d, J =2.7 Hz, 1H), 7.53 minutes (3 (t, J = 1.3 Hz, 2H), 6.88 (d, J = 8.8minute run). Hz, 1H).

Example 10N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(10)

Step 1:2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicAcid

To a pressure flask was added6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (4.48 g, 15.61 mmol),2-methyl-4-(trifluoromethoxy)phenol (3 g, 15.61 mmol), cesium carbonate(5.1 g, 15.65 mmol), and toluene (90 mL). The mixture was degassed withN₂ for 10 min, then copper (I) iodide (600 mg, 3.15 mmol) added. Theflask was flushed with N₂, sealed, and heated at 100° C. with vigorousstirring for 1 hour. The mixture was allowed to cool to RT and thendiluted with ethyl acetate and water. The water layer was acidified withHCl (32 mL of 1 M, 32.00 mmol) and the product extracted into ethylacetate. The organic phase was washed with brine, dried over sodiumsulfate, filtered and concentrated. To the resulting the oil was addedminimal dichloromethane and hexane to form an off white precipitate. Thesolid was filtered, washed with hexane and dried to provide2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (6.1 g, 98%) as a white solid. ESI-MS m/z calc. 398.04, found 399.0(M+1)+; retention time (Method A): 0.76 minutes (1.2 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 14.17 (s, 1H), 7.80 (t, J=8.6 Hz, 1H), 7.46 (d,J=2.9 Hz, 1H), 7.31 (dd, J=8.9, 2.9 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H),6.68 (d, J=8.9 Hz, 1H), 2.18 (s, 3H) ppm.

Step 2:2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride

To a solution of2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (800 mg, 2.01 mmol) and N,N-dimethylformamide (35 μL, 0.45 mmol) indichloromethane (8 mL) at 0° C. was added oxalyl chloride (900 μL, 10.32mmol) dropwise. The mixture was allowed to warm to room temperature andstirred 30 minutes. The solvent was evaporated under reduced pressure toafford2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride as a yellow solid, which was used in the next step withoutfurther purification.

Step 3:N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(10)

To a solution of 5-amino-2-fluoro-benzamide (37 mg, 0.24 mmol) indichloromethane (1 mL) was added DIEA (approximately 93.06 mg, 125.4 μL,0.7200 mmol) and the mixture was cooled to 0° C. To this solution wasadded a cold solution of2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (100 mg, 0.24 mmol) in dichloromethane (1 mL) dropwise. Thereaction was allowed to come to room temperature then stirred for 16hours. The mixture was concentrated, then dissolved in 2 mL DMSO andpurified by reverse phase HPLC to provideN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(551 mg, 48%). ESI-MS m/z calc. 534.0826, found 535.1 (M+1)+; retentiontime (Method B): 1.9 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.06 (s, 1H), 7.98 (dd, J=6.4, 2.8 Hz, 1H), 7.82 (t, J=8.7 Hz, 1H),7.76 (ddd, J=9.2, 4.5, 3.0 Hz, 2H), 7.70 (s, 1H), 7.43 (d, J=2.8 Hz,1H), 7.36-7.24 (m, 3H), 6.70 (d, J=8.9 Hz, 1H), 2.18 (s, 3H) ppm.

The compounds set forth in Table 6 were prepared by methods analogous tothe preparation of compound 10.

TABLE 6 Additional Compounds Prepared By Methods Analogous to Example 10Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 594-[[2-fluoro-6-[2-methyl-4- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δ(trifluoromethoxy)phenoxy]-3- 517.09, found 11.50 (s, 1H), 8.56 (d, J =5.5 Hz, (trifluoromethyl)benzoyl]ami- 518.1 (M + 1)+; 1H), 8.32 (d, J =2.1 Hz, 1H), 8.13 no]pyridine-2-carboxamide Retention time (d, J = 2.7Hz, 1H), 7.86 (t, J = 8.7 (Method B): 1.87 Hz, 1H), 7.82 (dd, J = 5.5,2.2 Hz, minutes (3 minute 1H), 7.69 (d, J = 2.9 Hz, 1H), 7.46- run).7.41 (m, 1H), 7.35-7.25 (m, 2H), 6.74 (d, J = 8.9 Hz, 1H), 2.18 (s, 3H).66 N-(4-carbamoyl-3-fluoro- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δphenyl)-2-fluoro-6-[2-methyl- 534.08, found 11.30 (s, 1H), 7.84 (t, J =8.6 Hz, 4-(trifluoromethoxy)phenoxy]- 535.1 (M + 1)+; 1H), 7.73 (d, J =8.5 Hz, 1H), 7.71- 3-(trifluoromethyl)benzamide Retention time 7.64 (m,1H), 7.60 (s, 1H), 7.56 (s, (Method B): 1.92 1H), 7.46-7.39 (m, 2H),7.32 (dd, J = minutes (3 minute 8.9, 2.7 Hz, 1H), 7.27 (d, J = 8.9 run).Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 2.18 (s, 3H).

Example 11N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(11)

Step 1: 2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicAcid

A solution of 6-bromo-2,3,4-trifluoro-benzoic acid (544 mg, 2.13 mmol),Cs₂CO₃ (1.4 g, 4.30 mmol), copper (I) iodide (92.3 mg, 0.4846 mmol),2-methoxy-4-(trifluoromethoxy)phenol (prepared as described in Example2, 675 mg, 3.24 mmol) and toluene (5.5 mL) was flushed with N₂ andstirred at 100° C. for 6 hours. After cooling to RT, water and ethylacetate were added to the mixture and the layers were separated. Theaqueous layer was acidified with concentrated HCl to ˜pH 1 and extractedwith ethyl acetate (3×). The combined organic phases were dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude material was purified by silica gel chromatography (ethylacetate/hexane gradient) to yield2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(143.6 mg, 18%). ESI-MS m/z calc. 382.0276, found 383.1 (M+1)+;retention time (Method B): 1.82 minutes (3 minute run).

Step 2:N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(11)

2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(140 mg, 0.37 mmol) and HATU (145 mg, 0.38 mmol) were combined inN,N-dimethylformamide (1.5 mL) and DIEA (128 μL, 0.73 mmol) and stirredfor 5 minutes. 5-Amino-2-fluoro-benzamide (57.1 mg, 0.3704 mmol) wasadded in one portion and the reaction was stirred at RT for 2.5 hours.The reaction was diluted with ethyl acetate and washed with saturatedaqueous sodium bicarbonate and brine. The organic layer was dried oversodium sulfate, filtered, and concentrated. The crude material waspurified by silica gel chromatography (ethyl acetate/hexane gradient)and re-purified using a reverse phase HPLC to yieldN-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(18.1 mg, 10%) as a white solid. ESI-MS m/z calc. 518.07, found 519.1(M+1)+; retention time (Method B): 1.73 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.96 (dd, J=6.4, 2.8 Hz, 1H),7.80-7.60 (m, 3H), 7.28 (dd, J=10.1, 8.9 Hz, 1H), 7.24 (d, J=8.8 Hz,1H), 7.18 (d, J=2.8 Hz, 1H), 7.06-6.90 (m, 1H), 6.90-6.76 (m, 1H), 3.78(s, 3H) ppm.

Example 12N-(2-Carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(12)N-(2-Carbamoyl-4-pyridyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(166)

Step 1: ethyl 3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate

3,5-difluoro-2-(trifluoromethyl)pyridine (4.87 g, 26.57 mmol) wasdissolved in anhydrous THF (20 mL) under a nitrogen atmosphere andcooled in a dry ice acetone bath (internal temperature −75° C.). Lithiumdiisopropylamide (15.94 mL of 2 M, 31.88 mmol) as a solution inTHF/heptane/benzene was further diluted with anhydrous THF (50 mL) andthis solution was added dropwise via pressure equalized addition funnelto the reaction mixture, not letting the internal temperature rise above−70° C. After complete addition the reaction mixture continued to stirfor 1 h with cooling resulting in a dark orange solution. Ethylchloroformate (6.9 mL, 72.16 mmol) as solution in THF (10 mL) was thenadded dropwise via pressure equalized addition funnel to the reactionmixture maintaining and internal temperature below −70° C. and stirredfor an additional 5 minutes at this temperature. The cooling bath wasremoved and the reaction was allowed to warm to warm to roomtemperature. After 25 minutes at room temperature the reaction wasquenched with saturated aqueous ammonium chloride. The mixture wasextracted with ethyl acetate, and the organic layer was washed withwater. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography (ethyl acetate/hexane gradient) to provideethyl 3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate (3.2 g,47%) as a clear liquid. ESI-MS m/z calc. 255.03, found 256.0 (M+1)+;retention time (Method A): 0.68 minutes (1.2 minute run). ¹H NMR (400MHz, DMSO-d6) δ 8.90 (s, 1H), 4.46 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz,3H) ppm.

Step 2: ethyl3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate

Ethyl 3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate (634 mg,2.49 mmol) was dissolved in anhydrous DMA (6 mL) under a nitrogenatmosphere and then cooled in an ice water bath.2-Methoxy-4-(trifluoromethoxy)phenol (prepared as described in Example2, 517 mg, 2.48 mmol) was added in one portion followed by Cs₂CO₃ (1.62g, 4.97 mmol). The reaction mixture was allowed to warm to roomtemperature and was stirred for 2 hours. The reaction mixture waspartitioned between ethyl acetate and water and the layers wereseparated. The organic layer was then washed with brine (3×), dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude material was purified by silica gel chromatography (ethylacetate/hexane gradient) to yield ethyl3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate(818 mg, 74%) as a white solid. ESI-MS m/z calc. 443.06, found 444.07(M+1)+; retention time (Method A): 0.85 minutes (1.2 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.28 (d,J=2.7 Hz, 1H), 7.04 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 4.37 (q, J=7.1 Hz,2H), 3.81 (s, 3H), 1.27 (t, J=7.1 Hz, 3H) ppm.

Step 3:3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicAcid

Ethyl3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate(620 mg, 1.40 mmol) was dissolved in methanol (9 mL) and then cooled inan ice water bath. Water (3 mL) was added followed by the addition ofNaOH (800 mg, 20.00 mmol) and the reaction was stirred with cooling for5 minutes. The cooling bath was removed and stirring continued as thereaction mixture was allowed to warm to room temperature and continuedto stir for 30 minutes. The solvents were removed under reduced pressureand the resulting solid was dissolved in water, cooled in an ice waterbath and treated with the dropwise addition of 6 M aqueous HCl until awhite solid formed. The resulting solid was collected by vacuumfiltration, washed with water and then further dried under reducedpressure to yield3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (470 mg, 81%). ESI-MS m/z calc. 415.02908, found 416.1 (M+1)+;retention time (Method C): 2.41 minutes (5 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 8.08 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H),7.03 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 3.81 (s, 3H) ppm.

Step 4: methyl4-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (240 mg, 0.58 mmol) in dichloromethane (4 mL) was added DMF (5 μL,0.065 mmol) and carefully oxalyl chloride (173 μL, 1.98 mmol) and themixture was allowed to warmed to room temperature over 3 hours. Thereaction mixture was concentrated under reduced pressure, dissolved indichloromethane (4 mL) and cooled in an ice bath. Methyl4-aminopyridine-2-carboxylate (prepared as described in Example 5, 115mg, 0.76 mmol) was added followed by triethylamine (431 μL, 3.09 mmol).The resulting mixture was allowed to warm to RT and stirred for 16hours. The reaction mixture was quenched with water (10 mL) andextracted with dichloromethane (2×10 mL). The combined organics weredried (MgSO₄), filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (ethylacetate/petroleum ether gradient) to give methyl4-[[3-fluoro-5-[2-methoxy-4-(tnfluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(182 mg, 57%). ESI-MS m/z calc. 549.0771, found 550.0 (M+1)+; retentiontime (Method D): 1.01 minutes (1.15 run).

Step 5:N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(12) andN-(2-Carbamoyl-4-pyridyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(166)

A solution of methyl4-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(182 mg, 0.33 mmol) in ammonia (5.3 mL of 7 M, 37.10 mmol) was stirredat RT overnight. The reaction was concentrated and the crude materialwas purified by achiral, normal phase SFC (DEAP Column (250×21.2 mm, 6 Å5 μm particle) made by Princeton (pn: 250212-01575) with a Gemini-NX(10×10 mm) guard column), isocratic run over 15.5 minutes. Mobile phaseA=Supercritical Liquid Carbon Dioxide (58-60 bar); Mobile phase B=5%Methanol with 20 mM Ammonium hydroxide; Flow rate=100 mL/min; injectionvolume=600 μL; Mass load 44 mg/injection; column temperature=40° C. Twoproducts were obtained as white solids:

N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(12, 17.53 mg, 10%). ESI-MS m/z calc. 534.08, found 535.0 (M+1)+;retention time (Method E): 3.22 minutes (4.45 minute run). ¹H NMR (400MHz, DMSO-d6) δ 11.58 (s, 1H), 8.58 (d, J=5.5 Hz, 1H), 8.40-8.06 (m,3H), 7.78 (dd, J=5.5, 2.2 Hz, 1H), 7.69 (d, J=2.8 Hz, 1H), 7.42 (d,J=8.8 Hz, 1H), 7.24 (d, J=2.7 Hz, 1H), 7.12-6.89 (m, 1H), 3.80 (s, 3H)ppm.

N-(2-Carbamoyl-4-pyridyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(166, 50 mg, 27%). ESI-MS m/z calc. 546.10, found 547.0 (M+1)+;retention time (Method E): 3.17 minutes (5 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 11.50 (s, 1H), 8.58 (s, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.12 (d,J=2.9 Hz, 1H), 7.97 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.68 (d,J=2.9 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.01(ddd, J=8.8, 2.8, 1.3 Hz, 1H), 3.97 (s, 3H), 3.80 (s, 3H) ppm.

Example 134-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(13)

Step 1: 6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl chloride

To 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5.4 g, 18.81 mmol)and N,N-dimethylformamide (125.9 mg, 1.722 mmol) in dichloromethane (54mL) at 0° C. was added oxalyl chloride (11.46 g, 90.29 mmol) dropwise.The mixture was stirred at room temperature for 5 hours under N₂atmosphere. The solvent was evaporated under reduced pressure to afford6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl chloride, which was used inthe next step without further purification.

Step 2:4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To 4-aminopyridine-2-carboxamide (2.559 g, 18.66 mmol) anddiisopropylethylamine (6.03 g, 46.65 mmol) in dichloromethane (28.5 mL)cooled at 0° C. was added dropwise a solution of6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl chloride (5.7 g, 18.66 mmol)in dichloromethane (28.5 mL). The mixture was stirred at roomtemperature overnight. Ethyl acetate (150 ml) was added to the mixturewas washed with water. The organic layer was dried over sodium sulfateand concentrated. Purification by silica gel chromatography(dichloromethane/methanol gradient) gave4-[[6-bromo-2-fluoro-3-ftrifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(800 mg, 11%). ESI-MS m/z calc. 406.97, found 408.2 (M+1)+; retentiontime (Method A): 0.58 minutes (1.2 minute run).

Step 3: 1-bromo-2-(difluoromethoxy)-4-(trifluoromethoxy)benzene

A mixture of 2-bromo-5-(trifluoromethoxy)phenol (5.5 g, 21.40 mmol),2-chloro-2,2-difluoro-acetate (sodium salt) (6.525 g, 42.80 mmol) andcesium carbonate (10.46 g, 32.10 mmol) in DMF (82.5 mL) was heated to100° C. for 2 hours. The mixture was diluted with dichloromethane,filtered, and the filtrate was washed with water and brine. The organiclayer was dried over MgSO₄, concentrated and purified by silica gelchromatography (ethyl acetate/hexane gradient) to give1-bromo-2-(difluoromethoxy)-4-(trifluoromethoxy)benzene (4.4 g, 67%) asa pale yellow liquid, which was used in the next step withoutpurification.

Step 4: 2-(difluoromethoxy)-4-(trifluoromethoxy)phenol

To 1-bromo-2-(difluoromethoxy)-4-(trifluoromethoxy)benzene (1.024 g,3.34 mmol) in dioxane (2.25 mL), in a microwave vial, was added KOH (562mg, 10.01 mmol) and water (1.126 mL). The mixture was degassed with N₂,and stirred under N₂ for ca. 2 minutes. Thendi-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (113.3 mg,0.267 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one:palladium (61mg, 0.067 mmol) were added. The mixture was purged with nitrogen, thevial capped and heated at 100° C. for 1 day. After cooling to RT, ethylether (30 mL) was added and the mixture was extracted with water. Thewater layer was acidified to approximately pH of 4 using 1N HCl andextracted with ether. The combined organic phases were washed withbrine, dried over sodium sulfate and concentrated to dryness underreduced pressure to obtain2-(difluoromethoxy)-4-(trifluoromethoxy)phenol (350 mg, 43%) as a darkoil, which was used in the next step without further purification.

Step 5:4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(13)

A microwave vial was charged with toluene (490 μL) (which was degassedprior to use with N₂ purge),4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(49 mg, 0.121 mmol), cesium carbonate (78.65 mg, 0.241 mmol) and2-(difluoromethoxy)-4-(trifluoromethoxy)phenol (29.46 mg, 0.121 mmol).The mixture was degassed with nitrogen. After ca. 2 minutes, copper (I)iodide (13.79 mg, 0.07241 mmol) was added and the reaction was stirredat 100° C. for 20 minutes. After cooling to RT, the reaction was dilutedwith ethyl acetate and water and the layers separated. The organic layerwas concentrated and dissolved in 2 mL of DMSO. Purification by reversephase HPLC gave4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(8.4 mg, 12%). ESI-MS m/z calc. 569.06, found 570.2 (M+1)+; retentiontime (Method B): 1.82 minutes (3 minute run).

Example 14N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide(14)

Step 1:6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicAcid

A pressure bottle was charged with6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5 g, 17.42 mmol),cesium carbonate (11.35 g, 34.84 mmol),3-chloro-4-(trifluoromethoxy)phenol (3.70 g, 17.42 mmol) and toluene(150 mL). The mixture was degassed with nitrogen. After ca. 2 minutes,copper (I) iodide (663.5 mg, 3.484 mmol) was added and the reaction wasstirred at 100° C. for 20 minutes. The mixture was diluted with ethylacetate and water, and the organic layer was washed with brine and driedover sodium sulfate. Trituration with hexane and filtration yielded6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (6.27 g, 86%). ESI-MS m/z calc. 417.98, found 419.1 (M+1)+;retention time (Method B): 1.93 minutes (3 minute run).

Step 2:6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride

To a slurry of6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (1.31 g, 3.13 mmol) and N,N-dimethylformamide (20 μL, 0.2583 mmol)in dichloromethane (13 mL) at 0° C. was added oxalyl chloride (1.5 mL,17.20 mmol) dropwise. The mixture was stirred at 0° C. for 20 minutesunder N₂ atmosphere. The ice bath was removed and the reaction wasstirred at room temperature for 35 minutes. The solvent was evaporatedunder reduced pressure to afford6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride, which was used in the next step without further purification.

Step 3:N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide(14)

To a solution of 5-amino-2-fluoro-benzamide (53 mg, 0.34 mmol) anddiisopropylethylamine (179 μL, 1.03 mmol) in dichloromethane (1 mL) at0° C. was added a slurry6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride (150 mg, 0.34 mmol) in dichloromethane (1 mL) slowly and themixture was stirred at room temperature for 1 hour. The solvent wasevaporated by blowing down with nitrogen. The crude product wasdissolved in DMSO, filtered and purified using a reverse phase HPLC toyieldN-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide(49.5 mg, 26%). ESI-MS m/z calc. 554.03, found 555.0 (M+1)+; retentiontime (Method C): 2.58 minutes (5 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.02 (s, 1H), 7.94 (dd, J=6.4, 2.8 Hz, 1H), 7.90 (t, J=8.6 Hz, 1H),7.76-7.69 (m, 3H), 7.69-7.64 (m, 1H), 7.63 (d, J=2.9 Hz, 1H), 7.34-7.25(m, 2H), 7.06 (d, J=8.8 Hz, 1H) ppm.

The compounds set forth in Table 7 were prepared by methods analogous tothe preparation of compound 14.

TABLE 7 Additional Compounds Prepared By Methods Analogous to Example 14Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 53 4-[[6-[3-chloro-4-ESI-MS m/z calc. ¹H NMR (500 MHz, DMSO-d₆) (trifluoromethoxy)phenoxy]-2-537.03, found 538.0 δ 11.50 (s, 1H), 8.56 (d, J = 5.5 fluoro-3- (M +1)+; Retention Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H),(trifluoromethyl)benzoyl]ami- time (Method C): 8.13 (s, 1H), 7.93 (t, J= 8.6 Hz, no]pyridine-2-carboxamide 2.54 minutes (5 1H), 7.80 (dd, J =5.6, 2.3 Hz, minute run). 1H), 7.71-7.63 (m, 3H), 7.34 (dd, J = 9.1, 2.9Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H)

Example 15N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(15)

Step 1:2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic Acid

To a solution of 4-(trifluoromethoxy)phenol (5.5 mL, 42.46 mmol),6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (10.0 g, 34.84 mmol),and cesium carbonate (22.73 g, 69.76 mmol) in toluene (75.0 mL, degassedwith N₂ purge prior to use) was added copper (I) iodide (1.6 g, 8.40mmol). The mixture was stirred at 100° C. for 1 hour. The mixture wascooled to RT and diluted with cold water (150 mL). The mixture wasacidified with 6N HCl (slight foaming) and diluted with ethyl acetate(150 mL). The biphasic mixture was filtered through celite to removeinsoluble inorganics. The aqueous phase was separated and extracted withethyl acetate (150 mL). The combined organic phases were washed with 150mL of brine, dried over MgSO₄, filtered and concentrated under reducedpressure affording an oil. The crude material was purified by silica gelchromatography (dichloromethane/methanol gradient), followed bycrystallization from heptane affording2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic acid(7.0 g, 52%) as an off-white solid. ESI-MS m/z calc. 384.02, found 385.1(M+1)+; retention time (Method B): 1.78 minutes (3 minute run). ¹H NMR(400 MHz, Chloroform-d3) δ 7.67-7.58 (m, 1H), 7.28 (dt, J=9.1, 1.0 Hz,2H), 7.19-7.10 (m, 2H), 6.70 (dd, J=8.9, 1.1 Hz, 1H) ppm.

Step 2:2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride

To a solution of2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic acid(700 mg, 1.82 mmol) and N,N-dimethylformamide (32 μL, 0.41 mmol) indichloromethane (7 mL) at 0° C. was added oxalyl chloride (800 μL, 9.17mmol) dropwise. The mixture was allowed to warm to room temperature andstirred for 30 minutes. The solvent was evaporated under reducedpressure to afford2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride, which was used in the next step without further purification.

Step 3:N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(15)

A vial charged with 5-amino-2-fluoro-benzamide (218 mg, 1.41 mmol) andDIEA (750 μL, 4.31 mmol) in THF (6 mL) was cooled at 0° C. under anatmosphere of N₂. A solution of2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (570 mg, 1.42 mmol) in THF (4 mL) and dichloromethane (3 mL)was added. The reaction mixture was gradually warmed to room temperatureand stirred for 1 hour. The mixture was quenched with water, and theaqueous layer was extracted with dichloromethane. The combined organiclayers were washed with 1N HCl (4×), dried over MgSO₄, filtered andconcentrated. The crude material was purified via silica gelchromatography (ethyl acetate/hexane gradient) to obtainN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(420 mg, 57%). ESI-MS m/z calc. 520.07, found 521.1 (M+1)+; retentiontime (Method B): 1.82 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.05 (s, 1H), 7.96 (dd, J=6.3, 2.8 Hz, 1H), 7.87 (t, J=8.6 Hz, 1H),7.75 (ddd, J=9.0, 4.5, 2.9 Hz, 2H), 7.69 (s, 1H), 7.49 (dq, J=7.8, 0.9Hz, 2H), 7.37-7.25 (m, 3H), 6.90 (d, J=8.8 Hz, 1H) ppm.

The compounds set forth in Table 8 were prepared by methods analogous tothe preparation of compound 15.

TABLE 8 Additional Compounds Prepared By Methods Analogous to Example 15Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 47N-(3-carbamoylphenyl)-2- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δfluoro-6-[4- 502.08, found 503.0 11.01 (s, 1H), 8.13 (t, J = 1.9 Hz,(trifluoromethoxy)phenoxy]- (M + 1)+; Retention 1H), 7.99 (s, 1H), 7.86(t, J = 8.7 3-(trifluoromethyl)benzamide time (Method B): Hz, 1H), 7.79(ddd, J = 8.0, 2.2, 1.0 1.79 minutes (3 Hz, 1H), 7.62 (dt, J = 7.8, 1.2Hz, minute run). 1H), 7.52-7.46 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.39(s, 1H), 7.35 (d, J = 9.1 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H) 484-[[2-fluoro-6-[4- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δ(trifluoromethoxy)phenoxy]- 503.07, found 504.0 11.47 (s, 1H), 8.55 (d,J = 5.4 Hz, 3-(trifluoromethyl)benzoyl]ami- (M + 1)+; Retention 1H),8.29 (d, J = 2.1 Hz, 1H), 8.11 no]pyridine-2-carboxamide time (MethodB): (d, J = 2.9 Hz, 1H), 7.90 (t, J = 8.7 1.79 minutes (3 Hz, 1H), 7.81(dd, J = 5.5, 2.2 Hz, minute run). 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.49(dd, J = 9.2, 1.0 Hz, 2H), 7.36 (d, J = 9.1 Hz, 2H), 6.92 (d, J = 8.9Hz, 1H) 134 N-(3-carbamoyl-4-chloro- ESI-MS m/z calc. ¹H NMR (400 MHz,DMSO-d6) δ phenyl)-2-fluoro-6-[4- 536.04, found 537.2 11.13 (s, 1H),7.93 (s, 1H), 7.87 (t, (trifluoromethoxy)phenoxy]- (M + 1)+; Retention J= 8.6 Hz, 1H), 7.76 (d, J = 2.6 Hz, 3-(trifluoromethyl)benzamide time(Method B): 1H), 7.68 (dd, J = 8.7, 2.6 Hz, 1H), 1.78 minutes (3 7.64(s, 1H), 7.52-7.45 (m, 3H), minute run). 7.35 (d, J = 9.1 Hz, 2H), 6.89(d, J = 8.9 Hz, 1H) 101 N-(3-carbamoyl-5-fluoro- ESI-MS m/z calc. ¹H NMR(400 MHz, DMSO-d6) δ phenyl)-2-fluoro-6-[4- 520.07, found 521.1 11.24(s, 1H), 8.06 (s, 1H), 7.91- (trifluoromethoxy)phenoxy]- (M + 1)+;Retention 7.85 (m, 2H), 7.75 (dt, J = 10.6, 2.23-(trifluoromethyl)benzamide time (Method B): Hz, 1H), 7.55 (s, 1H),7.51-7.44 1.83 minutes (3 (m, 3H), 7.38-7.27 (m, 2H), 6.91 minute run).(d, J = 8.8 Hz, 1H) 60 5-[[2-fluoro-6-[4- ESI-MS m/z calc. ¹H NMR (400MHz, DMSO-d6) δ (trifluoromethoxy)phenoxy]- 503.07, found 504.1 11.41(s, 1H), 8.84 (dd, J = 2.5, 0.7 3-(trifluoromethyl)benzoyl]ami- (M +1)+; Retention Hz, 1H), 8.27 (dd, J = 8.6, 2.5 Hz,no]pyridine-2-carboxamide time (Method B): 1H), 8.09-8.02 (m, 2H), 7.90(t, J = 1.77 minutes (3 8.6 Hz, 1H), 7.60 (d, J = 2.8 Hz, minute run).1H), 7.52-7.45 (m, 2H), 7.40- 7.32 (m, 2H), 6.94 (d, J = 8.8 Hz, 1H). 85N-(3-carbamoyl-4-hydroxy- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δphenyl)-2-fluoro-6-[4- 518.07, found 519.2 12.41 (s, 1H), 10.72 (s, 1H),8.32 (trifluoromethoxy)phenoxy]- (M + 1)+; Retention (s, 1H), 8.04 (d, J= 2.7 Hz, 1H), 3-(trifluoromethyl)benzamide time (Method B): 7.84 (t, J= 8.6 Hz, 2H), 7.57-7.46 1.77 minutes (3 (m, 3H), 7.40-7.30 (m, 2H),6.89 minute run). (dd, J = 8.8, 4.5 Hz, 2H). 264N-(4-carbamoylphcnyl)-2- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δfluoro-6-(4- 502.34, found 503.1 11.10 (s, 1H), 7.92 (br s, 1H),(trifluoromethoxy)phenoxy)- (M + 1)+; Retention 7.91-7.84 (m, 3H),7.74-7.68 3-(trifluoromethyl)benzamide time (Method B): (m, 2H),7.53-7.45 (m, 2H), 7.38- 1.76 minutes (3 7.34 (m, 2H), 7.32 (br s, 1H),minute run). 6.91 (d, J = 8.8 Hz, 1H).

Example 16N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(16)

2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 2, 109 mg, 0.26 mmol) and HATU(111 mg, 0.29 mmol) were dissolved in DMF (1.5 mL) and DIEA (102 μL,0.58 mmol) and the mixture was stirred for 10 minutes.4-Amino-2-fluoro-benzamide (45 mg, 0.29 mmol) was then added and thereaction was stirred at 45° C. for 16 h. The crude material was purifiedby silica gel chromatography (dichloromethane/methanol gradient), andfurther purified using reverse phase HPLC to provideN-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(6.4 mg, 4%). ESI-MS m/z calc. 550.0775, found 551.1 (M+1)+; retentiontime (Method B): 1.85 minutes (3 minute run).

Example 174-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(17)

Step 1:2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicAcid

To a solution of methyl 2,6-difluoro-4-(trifluoromethyl)benzoate (1000mg, 4.16 mmol) in DMF (12 mL) was added2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (prepared as describedin Example 1, 880 mg, 4.168 mmol) and Cs₂CO₃ (4.10 g, 12.58 mmol) andthe mixture was heated at 70° C. for 20 minutes. The reaction wasdiluted with ethyl acetate and washed with water and brine. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by silica gelchromatography (ethyl acetate/hexane gradient) to yield methyl2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate.ESI-MS m/z calc. 431.0683, found 432.2 (M+1)+; Retention time: 0.81minutes. A solution of this material in cold methanol (8 mL) was treatedwith cold aqueous NaOH (8.5 mL of 1 M, 8.500 mmol). The cloudy whitereaction mixture was allowed to come to room temperature then heated at55° C. for 1 h. The crude reaction was partitioned between 1 N HCl anddichloromethane. The dichloromethane phase was dried over sodiumsulfate, filtered and concentrated to a viscous oil. The oil wassuspended in hexane and stirred to form a thick precipitate. The solidwas filtered and air dried to provide2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (1.321 g, 75%) as a white solid. ESI-MS m/z calc. 417.05, found418.1 (M+1)+; retention time (Method B): 1.82 minutes (3 minute run). ¹HNMR (400 MHz, DMSO-d6) δ 14.09 (s, 1H), 7.57 (dd, J=8.9, 1.4 Hz, 1H),7.29-7.22 (m, 2H), 7.01 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.77 (s, 1H) ppm.

Step 2:2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoylchloride

A solution of2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (400 mg, 0.94 mmol) in dichloromethane (8 mL) was cooled using anice-bath. To this was added DMF (15 μL, 0.194 mmol) followed by carefuladdition of oxalyl chloride (200 μL, 2.29 mmol). The solution wasstirred for 10 min then removed from the ice bath and allowed to warm toroom temperature over 20 minutes. The reaction was concentrated underreduced pressure and azeotroped with dichloromethane to afford2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoylchloride, which was used directly in the next step.

Step 3:4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(17)

4-Aminopyridine-2-carboxamide (32 mg, 0.23 mmol) was dissolved in NMP (1mL) and DIEA (100 μL, 0.57 mmol) and then cooled to 0° C. To this wasadded dropwise a cold solution of freshly prepared2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoylchloride (100 mg, 0.23 mmol) in dichloromethane (3 mL). The reaction wasallowed to warm to room temperature and stirred for 16 hours. Reversephase HPLC purification provided4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(30.3 mg, 25%). ESI-MS m/z calc. 536.101, found 537.2 (M+1)+; retentiontime (Method B): 1.75 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.41 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.10(d, J=2.7 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.72-7.62 (m, 2H), 7.33(d, J=8.8 Hz, 1H), 7.22 (dd, J=2.7, 0.8 Hz, 1H), 7.01 (ddd, J=8.8, 2.8,1.3 Hz, 1H), 6.86 (s, 1H) ppm.

The compounds set forth in Table 9 were prepared by methods analogous tothe preparation of compound 17.

TABLE 9 Additional Compounds Prepared By Methods Analogous to Example 17Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 154 5-[[2-fluoro-6-[2-ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δ (trideuteriomethoxy)-4-536.10, found 537.2 11.33 (s, 1H), 8.85 (dd, J = 2.5, 0.7(trifluoromethoxy)phenoxy]-4- (M + 1)+; Retention Hz, 1H), 8.26 (dd, J =8.6, 2.5 Hz, (trifluoromethyl)benzoyl]ami- time (Method B): 1H),8.08-8.04 (m, 1H), 8.02 (d, J = no]pyridine-2-carboxamide 1.75 minutes(3 2.3 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), minute run). 7.57 (d, J = 1.7Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.01 (ddd,J = 8.8, 2.7, 1.2 Hz, 1H), 6.87 (s, 1H).

Example 18N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(18)

Step 1:2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicAcid

A pressure bottle was charged with6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5 g, 17.42 mmol),cesium carbonate (11.35 g, 34.84 mmol) and3-fluoro-4-(trifluoromethoxy)phenol (3.416 g, 17.42 mmol) in toluene(125 mL). The mixture was degassed with nitrogen. After ca. 2 minutes,copper (I) iodide (664 mg, 3.48 mmol) was added and the reaction wasstirred at 100° C. for 20 minutes. The reaction was diluted with ethylacetate and water. The phases were separated and the organic phase waswashed with brine and dried over sodium sulfate. Trituration with hexaneand filtration gave2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (4.7 g, 67%), which was used without further purification. ESI-MSm/z calc. 402.01, found 403.2 (M+1)+; retention time (Method B): 1.86minutes (3 minute run).

Step 2:2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride

To2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (900 mg, 2.24 mmol) and N,N-dimethylformamide (16 μL, 0.21 mmol) indichloromethane (10.5 mL) at 0° C. was added oxalyl chloride (952 μL,10.91 mmol) dropwise. The mixture was stirred at room temperature for 20minutes at 50° C. under a N₂ atmosphere. The solvent was evaporatedunder reduced pressure to afford2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (940 mg, 100%), which was used in the next step without furtherpurification.

Step 3:N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(18)

To 5-amino-2-fluoro-benzamide (55 mg, 0.36 mmol) anddiisopropylethylamine (186 μL, 1.07 mmol) in dichloromethane (1.5 mL)cooled at 0° C. was added dropwise a solution of2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (150 mg, 0.3566 mmol) in dichloromethane (1.5 mL). The reactionwas stirred at room temperature overnight. The mixture as diluted withethyl acetate (30 mL) washed with water, saturated aqueous sodiumbicarbonate and brine, dried over sodium sulfate and concentrated todryness. Purification by silica gel chromatography (ethyl acetate/hexanegradient) yieldedN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(117.5 mg, 60%). ESI-MS m/z calc. 538.06, found 539.1 (M+1)+; retentiontime (Method B): 1.82 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.03 (s, 1H), 8.03-7.84 (m, 2H), 7.82-7.61 (m, 4H), 7.49 (dd, J=11.0,2.9 Hz, 1H), 7.34-7.22 (m, 1H), 7.19-7.11 (m, 1H), 7.07 (d, J=8.8 Hz,1H) ppm.

Example 19N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide(19)

Step 1: 2-fluoro-5-(1,1,2,2,2-pentafluoroethyl)benzoic Acid

Bronze copper powder (20 g) was stirred in a solution of iodine (4 g) inacetone (250 mL) for 15 minutes until the iodine solution wasdecolorized. The product was collected in a filter funnel and added to asolution of concentrate HCL in acetone (1:1, v/v, 80 mL). After stirringfor 5 minutes, it was filtered and the solids were washed with acetone(8×40 ml) and dried for 30 minutes. The material was used directly inthe next step.

5-bromo-2-fluoro-benzoic acid (5 g, 22.83 mmol) was dissolved indimethyl sulfoxide (100 mL) at RT under a N₂ atmosphere and cooled to 0°C. A tank of 1,1,1,2,2-pentafluoro-2-iodo-ethane was cooled and then1,1,1,2,2-pentafluoro-2-iodo-ethane (39.3 g, 159.8 mmol) was transferredinto the reaction flask under N₂. A mixture of activated copper (freshlyprepared, 12.25 g, 192.8 mmol) was added and the flask was sealed underN₂ and heated for 30 minutes at 100° C. The temperature was raised to120° C. and stirred for 48 h. The mixture was cooled to RT and wasfiltered. The cake was washed with 60 mL DMSO and the filtrate wasdiluted with ethyl acetate (450 mL) and re-filtered through a plug ofCelite (3×). To the filtrate was added 1 N HCl and the layers wereseparated. The aqueous phase was extracted several times with ethylacetate. The organic phases were combined, dried over Na₂SO₄, filteredand the solvent was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate, washed with water (2×) and brine, dried overNa₂SO₄, filtered and the solvent was evaporated under reduced pressure.The crude material was purified by silica gel chromatography (ethylacetate/dichloromethane gradient) to yield2-fluoro-5-(1,1,2,2,2-pentafluoroethyl)benzoic acid (2.06 g, 35%) as alight brown solid. ESI-MS m/z calc. 258.01, found 259.2 (M+1)+;retention time (Method B): 1.36 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 13.84 (s, 1H), 8.11 (dd, J=6.6, 2.7 Hz, 1H), 8.07-7.96 (m,1H), 7.81-7.41 (m, 1H) ppm.

Step 2:2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzoicAcid

A mixture of 2-fluoro-5-(1,1,2,2,2-pentafluoroethyl)benzoic acid (500mg, 1.94 mmol), cesium carbonate (1.358 g, 4.16 mmol),N,N-dimethylformamide (10 mL) and 2-methoxy-4-(trifluoromethoxy)phenol(prepared as described in Example 2, 448 mg, 2.15 mmol) was heated at150° C. for 6 hours. The mixture was diluted with water and ethylacetate and the layers were separated. The aqueous layer was acidifiedwith 1 N HCl and extracted with ethyl acetate. The combined organicphases were washed with water and brine, dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by silica gelchromatography (ethyl acetate/dichloromethane gradient) to yield2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzoicacid (272.9 mg, 32%) as a yellow viscous solid. ESI-MS m/z calc. 446.04,found 447.0 (M+1)+; retention time (Method B): 2.01 minutes (3 minuterun).

Step 3:2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzoylchloride

To a solution of2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzoicacid (257 mg, 0.58 mmol) and N,N-dimethylformamide (10 μL, 0.13 mmol) indichloromethane (3 mL) at 0° C. was added oxalyl chloride (350 μL, 4.01mmol) dropwise. The ice bath was removed and the reaction was stirredunder a N₂ atmosphere for 35 min. The solvent was evaporated underreduced pressure to afford2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzoylchloride, which was used in the next step without further purification.

Step 4:N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide(19)

A solution of 5-amino-2-fluoro-benzamide (30 mg, 0.19 mmol) anddiisopropylethylamine (100 μL, 0.5766 mmol) in tetrahydrofuran (1 mL) at0° C. was added to a slurry of2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzoylchloride (89 mg, 0.19 mmol) in tetrahydrofuran (1 mL) slowly at 0° C.and the reaction was stirred at room temperature for 4 hours. Thesolvent was evaporated by blowing down with nitrogen. The crude productwas dissolved in DMSO, filtered and purified by reverse phase HPLC toyieldN-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide(25.7 mg, 23%). ESI-MS m/z calc. 582.08, found 583.0 (M+1)+; retentiontime (Method B): 2.04 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.62 (s, 1H), 8.00 (dd, J=6.5, 2.8 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H),7.83 (ddd, J=9.0, 4.4, 2.8 Hz, 1H), 7.78-7.62 (m, 3H), 7.44 (d, J=8.8Hz, 1H), 7.32-7.24 (m, 2H), 7.07 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.87 (d,J=8.8 Hz, 1H), 3.78 (s, 3H) ppm.

The compounds set forth in Table 10 were prepared by methods analogousto the preparation of compound 19.

TABLE 10 Additional Compounds Prepared By Methods Analogous to Example19 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 814-[[2-[2-methoxy-4- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6)(trifluoromethoxy)phenoxy]- 565.09, found 566.0 δ 11.07 (s, 1H), 8.54(d, J = 5.5 5-(1,1,2,2,2- (M + 1)+; Retention Hz, 1H), 8.34 (d, J = 2.2Hz, 1H), pentafluoroethyl)benzoyl]ami- time (Method B): 199 8.12 (d, J =2.9 Hz, 1H), 7.96 (d, no]pyridine-2-carboxamide minutes (3 minute J =2.5 Hz, 1H), 7.90 (dd, J = 5.5, run). 2.2 Hz, 1H), 7.77 (dd, J = 8.9,2.5 Hz, 1H), 7.66 (d, J = 2.7 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.25(d, J = 2.6 Hz, 1H), 7.12-7.03 (m, 1H), 6.90 (d, J = 8.6 Hz, 1H), 3.78(s, 3H).

Example 204-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(20)

Step 1: methyl 4-(difluoromethoxy)-2,6-difluoro-benzoate

To a suspension of 4-(difluoromethoxy)-2,6-difluoro-benzoic acid (900mg, 4.02 mmol) in dichloromethane (10 mL) and MeOH (3.5 mL, 86.40 mmol)under N₂ at 0° C. was added diazomethyl(trimethyl)silane (3.4 mL of 2 Msolution in hexanes, 6.80 mmol) dropwise (persistent yellow color). Themixture was stirred for 10 minutes then several drops of acetic acidwere added to quench excess reagent (resulting in a colorless solution).The mixture was concentrated, dissolved in dichloromethane and washedwith saturated aqueous NaHCO₃, dried over MgSO₄ and concentrated. Thecrude material was purified by silica gel column chromatography (ethylacetate/dichloromethane gradient) to yield methyl4-(difluoromethoxy)-2,6-difluoro-benzoate (746 mg, 74%). ¹H NMR (400MHz, DMSO-d6) δ 7.43 (t, J=72.6 Hz, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.21(d, J=1.9 Hz, 1H), 3.88 (s, 3H) ppm.

Step 2: methyl4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A vial charged with 2-methoxy-4-(trifluoromethoxy)phenol (prepared asdescribed in Example 2, 442 mg, 2.12 mmol), methyl4-(difluoromethoxy)-2,6-difluoro-benzoate (505 mg, 2.12 mmol), Cs₂CO₃ (2g, 6.14 mmol) and DMF (7 mL) was heated at 80° C. for 30 minutes. Thereaction mixture was quenched with ethyl acetate and brine and thelayers were separated. The organic layer was washed with brine (3×),dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude material was purified by silica gel chromatography(ethyl acetate/hexane gradient) to yield methyl4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(640 mg, 71%). ESI-MS m/z calc. 426.05, found 427.2 (M+1)+; retentiontime (Method B): 1.98 minutes (3 minute run).

Step 3:4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

To a solution of methyl4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(640 mg, 1.50 mmol) in MeOH (6 mL) was added NaOH (1.1 g, 27.50 mmol) inwater (6 mL). The reaction mixture was stirred at room temperature for15 hours. The solvent was evaporated and the reaction mixture wasquenched with 6N HCl. The aqueous layer was extracted with ethylacetate, dried over MgSO₄, filtered and concentrated to give4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (550 mg, 89%), which was used in the next step without furtherpurification. ESI-MS m/z calc. 412.04, found 413.0 (M+1)+; retentiontime (Method A): 0.67 minutes (1.2 minute run).

Step 4:4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(20)

A vial was charged with4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (100 mg, 0.24 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Example 2, 81 mg, 0.25 mmol),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (4.2 mg, 0.0118 mmol) in2-propanol (1.5 mL) and was heated at 83° C. under an air atmosphere for24 hours. The reaction mixture was cooled to room temperature, thesolvent evaporated and the residue was taken up in dichloromethane andwashed with 1N HCl. The organic layer was dried over MgSO₄, filtered andconcentrated. The crude material was purified by silica gelchromatography (ethyl acetate/hexane gradient) to yield4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(75 mg, 58%). ESI-MS m/z calc. 531.09, found 532.2 (M+1)+; retentiontime (Method B): 1.65 minutes (3 minute run). ¹H NMR (400 MHz, DMF-d7) δ11.69 (s, 1H), 8.96 (d, J=5.5 Hz, 1H), 8.72 (d, J=2.1 Hz, 1H), 8.51 (d,J=2.9 Hz, 1H), 8.25 (dd, J=5.5, 2.2 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H),7.96-7.54 (m, 3H), 7.50 (dd, J=10.1, 2.2 Hz, 1H), 7.43 (ddd, J=8.7, 2.7,1.3 Hz, 1H), 6.79 (d, J=1.8 Hz, 1H), 4.20 (s, 3H) ppm.

Example 21N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(21)

Step 1:2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicAcid

A pressure bottle was charged with 2-fluoro-4-(trifluoromethoxy)phenol(1.23 g, 6.29 mmol), cesium carbonate (4.31 g, 13.24 mmol) and6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (1.9 g, 6.62 mmol) intoluene (47 mL). The mixture was degassed with nitrogen. After ca. 2minutes, copper (I) iodide (252.2 mg, 1.324 mmol) was added and thereaction was stirred at 110° C. for 40 minutes. The reaction was dilutedwith ethyl acetate (100 mL) and water (30 mL) and the layers separated.The organic layer was washed with brined and dried over sodium sulfate.Trituration with hexane and filtration of the solid yielded2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (2.1 g, 79%). ESI-MS m/z calc. 402.01, found 403.1 (M+1)+;retention time (Method A): 0.73 minutes (1.2 minute run). ¹H NMR (400MHz, DMSO-d6) δ 7.76-7.46 (m, 1H), 7.42 (s, 1H), 7.25 (s, 2H), 6.76 (d,J=8.6 Hz, 1H) ppm.

Step 2:N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(21)

2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (1.45 g, 3.60 mmol) in dichloromethane (14.5 mL) was treated withDMF (14 μL, 0.18 mmol), cooled in an ice bath and treated dropwise withoxalyl chloride (505 μL, 5.79 mmol). The yellow solution was stirred atroom temperature for 1 hour and in a warm water bath for 0.5 hour tillno further gas evolution was observed. The solution was evaporated, andthe residue dissolved in dry dichloromethane (14.5 mL) to give a paleyellow solution of the acid chloride, which was used directly in thenext step.

5-Amino-2-fluoro-benzamide (667 mg, 4.33 mmol) in dichloromethane (14.5mL) was treated with diisopropylethylamine (1.6 mL, 9.19 mmol) and thesuspension was cooled in an ice bath and treated dropwise with the acidchloride solution. The fine suspension was stirred in the ice bath for 1hour and at room temperature for 1 h. The solution was washed with water(2×50 mL) and the aqueous phases were back extracted once withdichloromethane (20 mL). The combined organic phases were dried,filtered and evaporated. The crude material was purified by silica gelchromatography (ethyl acetate/hexane gradient) to giveN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(1089 mg, 56%) as a white solid. ESI-MS m/z calc. 538.06, found 539.0(M+1)+; retention time (Method C): 2.55 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.97 (dd, J=6.3, 2.8 Hz, 1H), 7.86(t, J=8.6 Hz, 1H), 7.80-7.62 (m, 4H), 7.52 (t, J=9.0 Hz, 1H), 7.36 (ddt,J=8.9, 2.5, 1.3 Hz, 1H), 7.29 (dd, J=10.1, 9.0 Hz, 1H), 6.94 (d, J=8.8Hz, 1H) ppm.

The compounds set forth in Table 11 were prepared by methods analogousto the preparation of compound 21.

TABLE 11 Additional Compounds Prepared By Methods Analogous to Example21 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 904-[[2-fluoro-6-[2-fluoro-4- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δ(trifluoromethoxy)phenoxy]- 521.06, found 521.9 11.52 (s, 1H), 8.56 (d,J = 5.5 Hz, 3- (M + 1)+; Retention 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.12(trifluoromethyl)benzoyl]ami- time (Method B): (d, J = 2.9 Hz, 1H), 7.90(t, J = 8.6 no]pyridine-2-carboxamide 1.77 minutes (3 Hz, 1H), 7.82 (dd,J = 5.5, 2.2 Hz, minute run). 1H), 7.77-7.62 (m, 2H), 7.55 (t, J = 9.0Hz, 1H), 7.44-7.31 (m, 1H), 6.97 (d, J = 8.8 Hz, 1H). 89N-(3-carbamoylphenyl)-2- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δfluoro-6-[2-fluoro-4- 520.07, found 521.2 11.05 (s, 1H), 8.14 (t, J =2.0 Hz, (trifluoromethoxy)phenoxy]- (M + 1)+; Retention 1H), 8.00 (s,1H), 7.86 (t, J = 8.7 3- time (Method B): Hz, 1H), 7.82-7.76 (m, 1H),7.72 (trifluoromethyl)benzamide 1.77 minutes (3 (dd, J = 10.8, 2.7 Hz,1H), 7.68- minute run). 7.59 (m, 1H), 7.53 (t, J = 9.0 Hz, 1H), 7.44 (t,J = 7.9 Hz, 1H), 7.41- 7.34 (m, 2H), 6.93 (d, J = 8.7 Hz, 1H).

Example 224-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(22)

Step 1: methyl4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A vial charged with methyl 4-bromo-2,6-difluoro-benzoate (500 mg, 1.99mmol), 2-methoxy-4-(trifluoromethoxy)phenol (prepared as described inExample 2, 415 mg, 1.99 mmol), Cs₂CO₃ (1.948 g, 5.98 mmol) and DMF (5mL) was heated at 80° C. for 1 hour. Ethyl acetate and brine were addedand the phases were separated. The organic phase was washed with brine(3×), dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude material was purified by silica gel chromatography(ethyl acetate/hexane gradient) to yield methyl4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (465mg, 53%). ESI-MS m/z calc. 437.9726, found 441.2 (M+2)+; retention time(Method A): 0.83 minutes (1.2 minute run).

Step 2: methyl4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A round bottom flask under a N₂ atmosphere, was charged with methyl4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (465mg, 1.06 mmol), bis(tri-t-butylphosphine)palladium(0) (180 mg, 0.35mmol), and THF (4.65 mL). The reaction mixture was cooled in an ice bathand bromo(cyclopropyl)zinc (4.3 mL of 0.5 M, 2.15 mmol), as a solutionin THF, was then added dropwise and the reaction was stirred for 30minutes. The reaction was quenched with saturated aqueous ammoniumchloride and the mixture was diluted with ethyl acetate. The layers wereseparated and the organic layer was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude material waspurified by silica gel chromatography (ethyl acetate/hexane gradient) toyield methyl4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(325 mg, 77%) as an off white. ESI-MS m/z calc. 400.09, found 401.3(M+1)+; retention time (Method B): 2.11 minutes (3 minute run).

Step 3:4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicAcid

To a slurry of methyl4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(325 mg, 0.81 mmol) in MeOH (3.2 mL) and water (3.2 mL) was added NaOH(350 mg, 8.75 mmol). The reaction mixture was stirred at roomtemperature for 5 hours. The solvent was evaporated and the residue wastaken up in water, cooled in an ice bath and quenched with 6N HClslowly. The resulting precipitated solid was filtered and washed withwater. The residue was dissolved in dichloromethane and ethyl acetate,dried over MgSO₄, filtered and concentrated. The filtrate was extractedwith ethyl acetate, dried over MgSO₄, concentrated and combined with theresidue to yield4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (275 mg, 88%). ESI-MS m/z calc. 386.08, found 387.3 (M+1)+;retention time (Method B): 1.87 minutes (3 minute run).

Step 4:4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(22)

A vial was charged with4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (80 mg, 0.207 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Example 4 μL, 69 mg, 0.21 mmol),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (3 mg, 0.008 mmol) in2-propanol (1.2 mL) and was heated at 80° C. under an atmosphere of airfor 20 hours. The mixture was cooled to room temperature, the solventevaporated and the residue was taken up in dichloromethane and washedwith 1N HCl. The organic layer was dried over MgSO₄, filtered andconcentrated. The crude material was purified by silica gelchromatography (ethyl acetate/hexane gradient) to yield4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(68 mg, 64%). ESI-MS m/z calc. 505.13, found 506.3 (M+1)+; retentiontime (Method B): 1.73 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.14 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.28 (d, J=2.1 Hz, 1H), 8.07(d, J=2.8 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.62 (d, J=2.9 Hz, 1H),7.23-7.10 (m, 2H), 7.01-6.89 (m, 1H), 6.75 (dd, J=10.6, 1.4 Hz, 1H),6.42 (d, J=1.2 Hz, 1H), 3.76 (s, 3H), 2.01-1.78 (m, 1H), 0.99-0.94 (m,2H), 0.78-0.51 (m, 2H) ppm.

Example 23N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(23)

Step 1: 2,5-difluoro-4-(trifluoromethyl)benzoyl chloride

To 2,5-difluoro-4-(trifluoromethyl)benzoic acid (2.00 g, 8.85 mmol) andN,N-dimethylformamide (63 μL, 0.81 mmol) in dichloromethane (23 mL) at0° C. was added oxalyl chloride (3.76 mL, 43.13 mmol) dropwise. Themixture was stirred at 50° C. for 40 minutes under a N₂ atmosphere. Thesolvent was evaporated under reduced pressure to afford2,5-difluoro-4-(trifluoromethyl)benzoyl chloride (1.9 g, 88%), which wasused in the next step without further purification.

Step 2:N-(3-carbamoyl-4-fluoro-phenyl)-2,5-difluoro-4-(trifluoromethyl)benzamide

To 5-amino-2-fluoro-benzamide (441 mg, 2.86 mmol) anddiisopropylethylamine (1.50 mL, 8.59 mmol) in dichloromethane (7 mL),cooled at 0° C., was added dropwise a solution of2,5-difluoro-4-(trifluoromethyl)benzoyl chloride (700 mg, 2.862 mmol) inTHF (7 mL). The reaction was stirred at room temperature overnight. Themixture was diluted with ethyl acetate (100 mL) and washed withsaturated aqueous NaHCO₃, water, and brine. The organic phase was driedover sodium sulfate and concentrated to dryness. The crude material waspurified by silica gel chromatography (ethyl acetate/hexane gradient) toyieldN-(3-carbamoyl-4-fluoro-phenyl)-2,5-difluoro-4-(trifluoromethyl)benzamide(1 g, 89%). ESI-MS m/z calc. 362.049, found 363.2 (M+1)+; retention time(Method A): 0.55 minutes (1.2 minute run).

Step 3:N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(23)

A mixture ofN-(3-carbamoyl-4-fluoro-phenyl)-2,5-difluoro-4-(trifluoromethyl)benzamide(90 mg, 0.23 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (prepared asdescribed in Example 2, 48 mg, 0.23 mmol), potassium carbonate (95 mg,0.69 mmol) and N,N-dimethylformamide (828 μL) was heated at 100° C.overnight. The mixture was filtered, and diluted with DMSO (1 mL). Thecrude material was purified by reverse phase HPLC to yieldN-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(21.9 mg, 17%) as a white solid. ESI-MS m/z calc. 550.08, found 551.2(M+1)+; retention time (Method B): 1.86 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.96 (dd, J=6.4, 2.8 Hz, 1H), 7.90(d, J=10.0 Hz, 1H), 7.79-7.64 (m, 3H), 7.28 (dd, J=10.1, 8.9 Hz, 1H),7.22 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.15 (d, J=5.6 Hz, 1H),6.98 (ddd, J=8.9, 2.7, 1.3 Hz, 1H), 3.77 (s, 3H) ppm.

Example 245-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(24)

Step 1:2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride

To a solution of2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 1, 500 mg, 1.20 mmol) andN,N-dimethylformamide (20 μL, 0.26 mmol) in dichloromethane (5 mL) at 0°C. was added oxalyl chloride (650 μL, 7.45 mmol) dropwise under N₂atmosphere. The reaction was removed from the ice bath after 10 min andstirred at RT for 30 minutes. The solvent was evaporated under reducedpressure to afford2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride which was used in the next step without further purification.

Step 2:5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(24)

A solution of 5-aminopyridine-2-carboxamide (248.6 mg, 1.813 mmol) indichloromethane (2.50 mL) and N,N-diisopropylethylamine (420 μL, 2.41mmol) was cooled to 0° C. A solution of ice cold2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride in dichloromethane (2.5 mL) was added slowly dropwise to thestirring amine solution. The mixture was removed from the ice bath after1 hour and stirred at RT for 69 hours. The reaction was diluted withdichloromethane and washed with water, 1 N HCl, saturated aqueous sodiumbicarbonate and brine. The organic layer was dried over Na₂SO₄, filteredand the solvent was evaporated under reduced pressure. The crudematerial was purified by silica gel chromatography (ethyl acetate/hexanegradient) to yield5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(326 mg, 51%) as a white solid. ESI-MS m/z calc. 536.10, found 537.0(M+1)+; retention time (Method C): 2.48 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.88 (d, J=2.5 Hz, 1H), 8.31 (dd,J=8.6, 2.5 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 8.03 (d, J=2.8 Hz, 1H), 7.81(t, J=8.6 Hz, 1H), 7.57 (d, J=2.8 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.25(d, J=2.8 Hz, 1H), 7.12-6.92 (m, 1H), 6.69 (d, J=8.9 Hz, 1H) ppm.

Example 25N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide(25)

Step 1: 2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzoic Acid

A microwave vial was charged 6-bromo-2-fluoro-3-(trifluoromethyl)benzoicacid (2.5 g, 8.71 mmol), cesium carbonate (5.676 g, 17.42 mmol) and4-fluorophenol (1.171 g, 10.45 mmol) in toluene (18.75 mL). The mixturewas degassed with nitrogen. After ca. 2 minutes, copper (I) iodide (332mg, 1.74 mmol) was added and the reaction was stirred at 100° C. for 25minutes. The reaction was diluted with 300 mL ethyl acetate and 200 mLof water and the phases were separated. The aqueous layer was acidifiedto approximately pH 3 and extracted with ethyl acetate. The combinedorganic phases were dried over sodium sulfate and concentrated. Thecrude material was purified by silica gel chromatography (ethylacetate/hexane gradient) to afford2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzoic acid (1.2 g,43%). ESI-MS m/z calc. 318.03, found 319.0 (M+1)+; retention time(Method A): 0.67 minutes (1.2 minute run).

Step 2: 2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzoyl chloride

To 2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzoic acid (570 mg,1.79 mmol) and N,N-dimethylformamide (11 μL, 0.141 mmol) indichloromethane (5.6 mL) at 0° C. was added oxalyl chloride (655 μL,7.51 mmol) dropwise. The mixture was stirred at 50° C. for 40 minutesunder an N₂ atmosphere. The solvent was evaporated under reducedpressure to afford2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzoyl chloride, whichwas used in the next step without further purification.

Step 3:N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide(25)

To 5-amino-2-fluoro-benzamide (37 mg, 0.24 mmol) anddiisopropylethylamine (124 μL, 0.71 mmol) in dichloromethane (390 μL)cooled at 0° C. was added dropwise a solution of2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzoyl chloride (80 mg,0.24 mmol) in dichloromethane (390 μL). The reaction was stirred at roomtemperature for 1 hour. The solvent was evaporated and the residue waspartitioned between water and ethyl acetate. The organic phase wasconcentrated to dryness. The residue was dissolved in 1 ml of DMSO andpurified by reverse phase HPLC to affordN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide(25.5 mg, 24%). ESI-MS m/z calc. 454.08, found 455.1 (M+1)+; retentiontime (Method B): 1.63 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.05 (s, 1H), 7.98 (dd, J=6.4, 2.8 Hz, 1H), 7.89-7.74 (m, 3H), 7.71(s, 1H), 7.40-7.25 (m, 5H), 6.79 (d, J=8.9 Hz, 1H) ppm.

The compounds set forth in Table 12 were prepared by methods analogousto the preparation of compound 15.

TABLE 12 Additional Compounds Prepared By Methods Analogous to Example15 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 504-[[2-fluoro-6-(4- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δfluorophenoxy)-3- 437.08, found 438.1 11.54 (s, 1H), 8.57 (d, J = 5.5Hz, (trifluoromethyl)benzoyl]ami- (M + 1)+; Retention 1H), 8.33 (d, J =2.2 Hz, 1H), 8.16 no]pyridine-2-carboxamide time (Method B): (s, 1H),7.92-7.82 (m, 2H), 7.71 1.61 minutes (3 (s, 1H), 7.39-7.26 (m, 4H), 6.80minute run). (d, J = 8.9 Hz, 1H). 49 N-(3-carbamoylphenyl)-2- ESI-MS m/zcalc. ¹H NMR (400 MHz, DMSO-d6) δ fluoro-6-(4-fluorophenoxy)-3- 436.08,found 437.1 11.00 (s, 1H), 8.15 (t, J = 1.9 Hz,(trifluoromethyl)benzamide (M + 1)+; Retention 1H), 8.00 (s, 1H),7.88-7.77 (m, time (Method B): 2H), 7.62 (dt, J = 7.9, 1.2 Hz, 1H), 1.59minutes (3 7.44 (t, J = 7.9 Hz, 1H), 7.40 (s, minute run). 1H),7.36-7.25 (m, 4H), 6.78 (d, J = 8.9 Hz, 1H).

Example 264-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(26)

Step 1: 6-bromo-2-fluoro-3-(trifluoromethoxy)phenol

To a solution of 2-fluoro-3-(trifluoromethoxy)phenol (3 g, 15.30 mmol)in dichloromethane (10 mL) and heptane (20 mL) cooled in an ice-bath wasadded 1-bromopyrrolidine-2,5-dione (3 g, 16.86 mmol) in 6 portions over1 hour. The reaction was stirred for a further hour at 0° C. and thenallowed to warm to RT. The reaction was filtered and the filtrate wasconcentrated under reduced pressure to yield6-bromo-2-fluoro-3-(trifluoromethoxy)phenol (3.7 g, 88%), which was usedwithout further purification. ESI-MS m/z calc. 275.925, found 274.8(M−1)−; retention time (Method D): 0.65 minutes (1.15 minute run).

Step 2: 1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene

To a solution of 6-bromo-2-fluoro-3-(trifluoromethoxy)phenol (3 g, 10.91mmol) in acetone (3 mL) was added iodomethane (2.38 g, 16.77 mmol) andpotassium carbonate (2.26 g, 16.35 mmol) and the mixture heated to 60°C. for 1 hour. The mixture was allowed to cool to RT and was dilutedwith dichloromethane (15 mL) and filtered. The filtrate was concentratedunder reduced pressure to yield an oil. The crude material was purifiedby silica gel chromatography (ethyl acetate/petroleum ether gradient) toyield 1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene (2.35 g,75%) as a white solid. ¹H NMR (500 MHz, Chloroform-d3) δ 7.36 (dd,J=9.1, 2.4 Hz, 1H), 6.97 (ddq, J=8.6, 7.2, 1.3 Hz, 1H), 4.05-4.00 (m,3H) ppm.

Step 3: 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol

To a solution of 1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene(1 g, 3.460 mmol) in dioxane (5 mL) was addeddi-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (75 mg, 0.18mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (80 mg, 0.087mmol) and KOH (582 mg, 10.37 mmol) followed by water (5 mL) and themixture heated to 90° C. for 3 hours. The reaction mixture was allowedto cool to RT and filtered. The aqueous layer was acidified toapproximately pH 1 with 2M HCl and was extracted with ethyl acetate(2×10 mL). The combined organic phases were washed with brine (5 mL),dried over magnesium sulfate and concentrated to dryness. The productwas purified by silica gel chromatography (ethyl acetate/petroleum ethergradient) to yield 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (514mg, 66%) as an oil. ESI-MS m/z calc. 226.025, found 224.9 (M−1)−;retention time (Method D): 0.87 minutes (1.15 minute run).

Step 4:2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicAcid

To a solution of 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (40 mg,0.18 mmol) in toluene (1 mL) was added copper (I) iodide (7 mg, 0.03676mmol), cesium carbonate (113 mg, 0.3468 mmol) and6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (50 mg, 0.1742 mmol)and the mixture heated to 100° C. for 6 hours. The reaction mixture wasallowed to cool to RT and HCl (270 μL of 2 M, 0.54 mmol) added slowly.The mixture was extracted with ethyl acetate (10 mL). The organic phasewas washed with brine (20 mL), dried over magnesium sulfate andconcentrated to dryness. The product was purified by silica gelchromatography (ethyl acetate/petroleum ether gradient) to yield2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (52 mg, 69%) as a white solid. ESI-MS m/z calc. 432.02, found 430.9(M−1)−; retention time (Method D): 0.76 minutes (1.15 minute run).

Step 5:4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(26)

To an ice-cooled solution of2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (60 mg, 0.14 mmol) in dichloromethane (10 mL) and DMF (6 μL, 0.077mmol) was carefully added oxalyl chloride (25 μL, 0.29 mmol) and themixture was warmed to room temperature over 30 minutes and stirred for afurther hour. The reaction mixture was concentrated under reducedpressure to afford a yellow solid. The residue was dissolved indichloromethane (10 mL) followed by the addition of4-aminopyridine-2-carboxamide (25 mg, 0.18 mmol) and triethylamine (60μL, 0.43 mmol). The resulting mixture was stirred at RT for 45 minutesand then concentrated under reduced pressure. The residue was purifiedby silica gel chromatography (ethyl acetate/petroleum ether gradient) toyield4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(4 mg, 4%) as a white solid. ESI-MS m/z calc. 551.07, found 552.0(M+1)+; retention time (Method E): 3.36 minutes (4.45 minute run).

Example 274-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(115)

To a stirring solution of4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(prepared as described in Example 6, 112 mg, 0.209 mmol) in anhydrousdichloromethane (1 mL) under N₂ atmosphere at 0° C. was added3-chloroperoxybenzoic acid (140 mg, 0.627 mmol). The reaction mixturewas allowed to warm to room temperature and stirred for 1 hour. Thereaction mixture was then cooled to 0° C., treated with additional3-chloroperoxybenzoic acid (70 mg, 0.31 mmol) and stirred at roomtemperature for 5 hours. The reaction mixture was again cooled to 0° C.,treated with 3-chloroperoxybenzoic acid (30 mg, 0.13 mmol) and stirredfor an additional 16 hours at room temperature. Dichloromethane wasadded to clarify the reaction and the resulting solution was stirred for1 hour. The solvent was removed in vacuo and the residue was purified bysilica gel chromatography (0-100% ethyl acetate/hexanes) to provide4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(80 mg, 69%) as a white solid. ESI-MS m/z calc. 552.10, found 553.0(M+1)+; retention time (Method B): 1.66 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.56 (s, 1H), 10.59 (d, J=4.6 Hz, 1H), 8.55 (d,J=3.3 Hz, 1H), 8.38 (d, J=7.1 Hz, 1H), 8.27 (d, J=4.6 Hz, 1H), 7.87 (dd,J=7.1, 3.3 Hz, 1H), 7.82 (t, J=8.7 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.26(d, J=2.8 Hz, 1H), 7.10-6.96 (m, 1H), 6.69 (d, J=8.9 Hz, 1H) ppm.

Example 284-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(137)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide

A solution of 2-bromo-5-methyl-pyridin-4-amine (406 mg, 2.17 mmol) indichloromethane (3 mL) and DIEA (500 μL, 2.87 mmol) was cooled to 0° C.A solution of cold2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (prepared as described in Example 1, Step 4) in dichloromethane(3 mL) was added dropwise to the stirring amine solution. The reactionmixture was removed from the ice bath after 30 minutes and stirred atroom temperature for 24 hours. The reaction was diluted withdichloromethane and washed with water, 1 M HCl, saturated aqueousNaHCO₃, and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-20% ethylacetate/hexanes) providedN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(551 mg, 65%) as a yellow solid. ESI-MS m/z calc. 585.02, found 586.0(M+1)+; retention time (Method C): 3.06 minutes (5 minute run).

Step 2: Methyl4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(550 mg, 0.938 mmol) was dissolved in methanol (15 mL), andtriethylamine (277 μL, 1.99 mmol) and Pd(dppf)Cl₂.DCM (152 mg, 0.186mmol) were added. Carbon monoxide was bubbled through the vigorouslystirring mixture for ˜16 minutes. The reaction vessel was sealed andheated to 75° C. for 22 hours. The reaction mixture was cooled, filteredthrough a pad of Celite eluting with methanol and concentrated in vacuo.Silica gel chromatography (0-100% ethyl acetate/dichloromethane)provided methyl4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(383 mg, 72%). ESI-MS m/z calc. 565.12, found 566.0 (M+1)+; retentiontime (Method C): 2.62 minutes (5 minute run).

Step 3:4-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(137)

A mixture of methyl4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(283 mg, 0.501 mmol) and ammonia (8 mL of 7 M in methanol, 56 mmol) wasstirred at room temperature for 23 hours. The reaction was concentratedin vacuo. Silica gel chromatography (0-30% ethylacetate/dichloromethane) provided4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(195 mg, 71%) as a white solid. ESI-MS m/z calc. 550.12, found 551.0(M+1)+; retention time (Method C): 2.5 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.48 (d, J=4.8 Hz, 2H), 8.06 (d,J=2.8 Hz, 1H), 7.80 (t, J=8.6 Hz, 1H), 7.61 (d, J=2.7 Hz, 1H), 7.38 (d,J=8.8 Hz, 1H), 7.28 (d, J=2.6 Hz, 1H), 7.16-6.95 (m, 1H), 6.65 (d, J=8.9Hz, 1H), 2.32 (s, 3H) ppm.

Example 296-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide(212)

Step 1: Methyl6-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxylate

2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 1, Step 3, 200 mg, 0.479 mmol)and HATU (201 mg, 0.527 mmol) were combined in DMF (2 mL) and DIEA (186mg, 251 μL, 1.44 mmol), and the mixture was stirred for 5 minutes.Methyl 6-aminopyridine-3-carboxylate (73 mg, 0.48 mmol) was added in oneportion and the reaction was stirred for 21 hours. Additional methyl6-aminopyridine-3-carboxylate (146 mg, 0.96 mmol) was added and thereaction mixture was heated at 80° C. for 3 hours. The reaction mixturewas filtered and purified by HPLC (10-99% acetonitrile/5 mM HCl) toprovide methyl6-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxylate(56 mg, 21%). ESI-MS m/z calc. 551.10, found 552.0 (M+1)+; retentiontime (Method A): 0.79 minutes (1 minute run).

Step 2:6-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide(212)

A mixture of methyl6-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxylate(56 mg, 0.10 mmol) and ammonia (6 mL of 7 M in methanol, 42 mmol) wasstirred at 60° C. for 17 hours. The reaction mixture was concentrated invacuo. The crude product was dissolved in DMSO, filtered and purifiedusing by HPLC (10-99% acetonitrile/5 mM HCl) to provide6-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide(16 mg, 29%). ESI-MS m/z calc. 536.10, found 537.0 (M+1)+; retentiontime (method C): 2.46 minutes (5 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 11.60 (s, 1H), 8.96-8.61 (m, 1H), 8.30 (dd, J=9.0, 2.3 Hz, 1H), 8.23(d, J=8.8 Hz, 1H), 8.07 (s, 1H), 7.76 (t, J=8.6 Hz, 1H), 7.50 (s, 1H),7.36 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.8 Hz, 1H), 7.12-6.90 (m, 1H), 6.64(d, J=8.9 Hz, 1H) ppm.

Example 306-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(168)

Step 1:N-(6-Bromo-2-pyridyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide

To a stirring slurry of 6-bromopyridin-2-amine (191 mg, 1.10 mmol) indichloromethane (3 mL) and DIEA (190 mg, 256 μL, 1.47 mmol) at 0° C. wasadded slurry of cold2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (prepared as described in Example 1, Step 4, 320 mg, 0.735mmol) in dichloromethane (3 mL) dropwise. The reaction mixture wasremoved from the ice bath after 10 min and stirred at room temperaturefor 18 hours. The solvent was evaporated in vacuo and the crude productwas dissolved in DMSO, filtered and purified by HPLC (10-99%acetonitrile/5 mM HCl) to provideN-(6-bromo-2-pyridyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(172 mg, 41%). ESI-MS m/z calc. 571.01, found 571.8 (M+1)⁺; retentiontime (Method A): 0.84 minutes (1 minute run).

Step 2: Methyl6-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-ftrifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

In a pressure tube,N-(6-bromo-2-pyridyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(171 mg, 0.299 mmol) was dissolved in methanol (6 mL) and triethylamine(84 μL, 0.60 mmol), and Pd(dppf)Cl₂.DCM (50 mg, 0.061 mmol) was added.Carbon monoxide was bubbled through the vigorously stirring reactionmixture for 15 minutes. The reaction vessel was sealed and heated to 75°C. for 14 hours. The reaction mixture was cooled, filtered through a padof Celite eluting with methanol and concentrated in vacuo. The crudematerial was purified by silica gel chromatography (0-30% ethylacetate/dichloromethane) to provide methyl6-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(126.9 mg, 77%) as a white solid. ESI-MS m/z calc. 551.10, found 552.0(M+1)+; retention time (Method C): 2.93 minutes (5 minute run).

Step 3:6-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(168)

A solution of methyl6-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(127 mg, 0.2303 mmol) and ammonia (3.6 mL of 7 M in methanol, 25.20mmol) was stirred at ambient temperature for 4 hours. The reaction wasconcentrated in vacuo. The crude material was purified by silica gelchromatography (0-30% ethyl acetate/dichloromethane) to provide6-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(99 mg, 80%) as a white solid. ESI-MS m/z calc. 536.10, found 537.0(M+1)+; retention time (Method C): 2.59 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.05 (t,J=7.9 Hz, 1H), 7.91-7.66 (m, 3H), 7.59 (s, 1H), 7.36 (d, J=8.8 Hz, 1H),7.25 (d, J=2.7 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H)ppm.

Example 315-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-4-methyl-pyridine-2-carboxamide(161)

Step 1: Methyl5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-4-methyl-pyridine-2-carboxylate

To a stirring slurry of methyl 5-amino-4-methyl-pyridine-2-carboxylate(183 mg, 1.10 mmol) in dichloromethane (3 mL) and DIEA (190 mg, 256 μL,1.47 mmol) at 0° C. was added slurry of cold2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (prepared as described in Example 1, Step 4, 320 mg, 0.735mmol) in dichloromethane (3 mL) dropwise. The reaction mixture wasremoved from the ice bath after 10 min and stirred at room temperaturefor 18 hours. The solvent was evaporated in vacuo and the crude productwas dissolved in DMSO, filtered and purified by HPLC (10-99%acetonitrile/5 mM HCl) to provide methyl5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-4-methyl-pyridine-2-carboxylate(360 mg, 87%). ESI-MS m/z calc. 565.12, found 566.0 (M+1)⁺; retentiontime (Method A): 0.72 minutes (1 minute run).

Step 2:5-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-4-methyl-pyridine-2-carboxamide(161)

A solution of methyl5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-4-methyl-pyridine-2-carboxylate(360 mg, 0.637 mmol) and ammonia (10 mL of 7 M in methanol, 70 mmol) wasstirred at room temperature for 16 hours. The reaction was concentratedin vacuo. The crude material was purified by silica gel chromatography(0-30% ethyl acetate/dichloromethane) to provide5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-4-methyl-pyridine-2-carboxamide(199 mg, 57%) as a white solid. ESI-MS m/z calc. 550.12, found 551.0(M+1)+; retention time (Method C): 2.5 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.71 (s, 1H), 8.06 (s, 1H), 7.97 (s,1H), 7.80 (t, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.29(d, J=2.8 Hz, 1H), 7.15-6.94 (m, 1H), 6.67 (d, J=8.8 Hz, 1H), 2.35 (s,3H) ppm.

Example 325-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-6-methyl-pyridine-2-carboxamide(188)

Step 1:N-(6-Bromo-2-methyl-3-pyridyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide

To a stirring solution of2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 1, Step 3, 200 mg, 0.479 mmol) indichloromethane (4 mL) at 0° C. was added DMF (6 μL, 0.08 mmol) followedby the dropwise addition of oxalyl chloride (84 μL, 0.96 mmol). Thesolution was stirred for 10 minutes then removed from the ice bath andallowed to warm to room temperature over 20 minutes. The reaction wasconcentrated in vacuo and azeotroped with dichloromethane to afford2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride as a white solid. The solid was redissolved in colddichloromethane (2 mL) and added dropwise to a stirring solution of6-bromo-2-methyl-pyridin-3-amine (99 mg, 0.53 mmol) in NMP (1 mL) andDIEA (250 μL, 1.44 mmol) at 0° C. The reaction was allowed to warm toroom temperature and was then diluted with dichloromethane and washedwith water and brine, dried over Na₂SO₄, filtered and concentrated invacuo. Silica gel chromatography (0-10% methanol/dichloromethane)providedN-(6-bromo-2-methyl-3-pyridyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(250 mg, 89%). ESI-MS m/z calc. 585.02, found 588.2 (M+1)+; retentiontime (Method B): 2.07 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.58 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.79 (t, J=8.7 Hz, 1H), 7.53(d, J=8.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.07(ddd, J=8.7, 2.6, 1.3 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 2.44 (s, 3H) ppm.

Step 2: Methyl5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-6-methyl-pyridine-2-carboxylate

N-(6-Bromo-2-methyl-3-pyridyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(230 mg, 0.392 mmol) was dissolved in methanol (8 mL) and triethylamine(115 μL, 0.825 mmol) in a pressure tube and Pd(dppf)Cl₂.DCM (65 mg,0.07959 mmol) was added. Carbon monoxide was vigorously bubbled throughthe reaction mixture for 5 minutes. The reaction vessel was sealed andheated to 75° C. for 2 hours. The reaction was cooled to roomtemperature and concentrated in vacuo. Purification by silica gelchromatography (0-30% ethyl acetate/dichloromethane) provided methyl5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-6-methyl-pyridine-2-carboxylateas a white solid. ESI-MS m/z calc. 565.11, found 566.3 (M+1)+; retentiontime (Method A): 0.74 minutes (1 minute run).

Step 3:5-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-6-methyl-pyridine-2-carboxamide(188)

A solution of methyl5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-6-methyl-pyridine-2-carboxylate(from Step 2) in methanol (4 mL) and ammonia (5.6 mL of 7 M in methanol,39.2 mmol) was stirred at room temperature for 16 hours. The reactionwas concentrated in vacuo and purified by silica gel chromatography(0-30% ethyl acetate/dichloromethane) to provide5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-6-methyl-pyridine-2-carboxamide(180 mg, 83% over 2 steps). ESI-MS m/z calc. 550.12, found 551.3 (M+1)+;retention time (Method B): 1.77 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 10.63 (s, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.96 (d, J=2.8 Hz,1H), 7.92 (d, J=8.2 Hz, 1H), 7.80 (t, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.38(d, J=8.8 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.07 (ddd, J=8.8, 2.8, 1.2Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 2.53 (s, 3H) ppm.

Example 335-Fluoro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(123) and5-Fluoro-4-(2-methoxy-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamido)picolinamide(128)

Step 1: Isopropyl5-fluoro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

Methyl4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]-5-fluoro-pyridine-2-carboxylate(prepared as described in Preparation 2, 84 mg, 0.23 mmol),2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 2, Step 3, 123 mg, 0.279 mmol)and tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (2 mg, 0.006 mmol) werecombined in 2-propanol (1.6 mL) and heated at reflux for 7 days. Thereaction mixture was concentrated in vacuo directly onto silica gel andpurified by silica gel chromatography (0-80% ethyl acetate/petroleumether) to provide isopropyl5-fluoro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(42 mg, 30%). ESI-MS m/z calc. 594.10, found 595.3 (M+1)+; 593.3 (M−1)−;retention time (Method F): 1.13 minutes (1.5 minute run).

Step 2:5-Fluoro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (123) and5-Fluoro-4-(2-methoxy-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamido)picolinamide(128)

A solution of isopropyl5-fluoro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(40 mg, 0.07 mmol) in ammonia (850 μL of 4 M in methanol, 3.4 mmol) wasstirred at room temperature for 24 hours then at 50° C. for 24 hours.The cooled reaction mixture was filtered and purified directly by HPLC(0-100% acetonitrile/0.05% TFA) to provide5-fluoro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(123, 14 mg, 35%) ESI-MS m/z calc. 551.07, found 551.8 (M+1)+; 549.9(M−1)−; Retention time (Method E): 3.34 minutes (5 minutes run). ¹H NMR(500 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.92 (d, J=6.4 Hz, 1H), 8.63 (d,J=2.2 Hz, 1H), 8.07 (d, J=2.6 Hz, 1H), 7.80 (t, J=8.6 Hz, 1H), 7.68 (d,1H), 7.36 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.07-7.01 (m, 1H),6.66 (d, J=8.9 Hz, 1H), 3.80 (s, 3H) ppm and5-fluoro-4-[[2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(128, 6 mg, 15%) ESI-MS m/z calc. 563.09, found 563.9 (M+1)+; 561.9(M−1)−; Retention time (Method E): 3.37 minutes (5 minutes run). ¹H NMR(500 MHz, DMSO-d₆) δ 11.23 (s, 1H), 8.91 (d, J=6.4 Hz, 1H), 8.62 (d,J=2.2 Hz, 1H), 8.09-8.05 (m, 1H), 7.69 (d, J=7.9 Hz, 2H), 7.33 (d, J=8.8Hz, 1H), 7.24 (d, J=2.7 Hz, 1H), 7.04 (dd, J=9.1, 2.4 Hz, 1H), 6.53 (d,J=8.9 Hz, 1H), 3.94 (s, 3H), 3.81 (s, 3H) ppm.

Example 344-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(120)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide

To solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 2, Step 3, 300 mg, 0.681 mmol) indichloromethane (5 mL) at 0° C. was added DMF (6 μL, 0.08 mmol) andoxalyl chloride (200 μL, 2.29 mmol) dropwise. The reaction mixture wasallowed to warm to room temperature over 3.5 hours then concentrated invacuo. The residue was dissolved in dichloromethane (5 mL) and cooled to0° C. The solution was treated with 2-bromo-5-methyl-pyridin-4-amine(165 mg, 0.882 mmol) followed by triethylamine (500 μL, 3.59 mmol). Theresulting mixture was allowed to warm to room temperature and stirredfor 48 hours. The reaction mixture was diluted with water (10 mL) andextracted with dichloromethane (2×10 mL). The combined organics weredried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-20% ethyl acetate/petroleum ether) providedN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(217 mg, 55%) as an off-white solid. ESI-MS m/z calc. 582.00, found585.1 (M+1)+; 583.1 (M−1)−; retention time (Method E): 1.15 minutes (5minute run). ¹H NMR (500 MHz, CDCl₃) δ 8.61 (s, 1H), 8.15 (s, 2H),7.60-7.57 (m, 1H), 7.23 (d, J=8.7 Hz, 1H), 6.98-6.96 (m, 1H), 6.94 (d,J=2.4 Hz, 1H), 6.53 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 2.17 (s, 3H); ¹⁹FNMR (471 MHz, CDCl₃) δ −58.01, −60.82 (d, J=13.0 Hz), −112.20 (q,J=14.3, 13.3 Hz) ppm.

Step 2: Methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tubeN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(217 mg, 0.372 mmol) was dissolved in methanol (10 mL) and triethylamine(110 μL, 0.789 mmol) and Pd(dppf)Cl₂.DCM (60 mg, 0.074 mmol) were added.Carbon monoxide was bubbled through the vigorously stirring reactionmixture for 5 minutes. The reaction vessel was sealed and heated to 75°C. for 16 hours. The reaction mixture was cooled to room temperature,filtered through a pad of Celite eluting with methanol and concentratedin vacuo. Silica gel chromatography (0-100% ethyl acetate/petroleumether) provided methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(178.6 mg, 85%). ESI-MS m/z calc. 562.10, found 563.2 (M+1)+; 561.2(M−1)−; retention time (Method F): 1.04 minutes (1.5 minute run). ¹H NMR(500 MHz, CDCl₃) δ 9.06 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 7.59 (d,J=17.0 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 6.98-6.96 (m, 1H), 6.94-6.93 (m,1H), 6.55 (d, J=9.4 Hz, 1H), 4.03 (s, 3H), 3.83 (s, 3H), 2.30 (s, 3H)ppm. ¹⁹F NMR (471 MHz, CDCl₃) δ −58.01, −60.82 (d, J=12.9 Hz),−112.16-−112.24 (m) ppm.

Step 3:4-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(120)

A mixture of methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(178 mg, 0.317 mmol) and ammonia (5 mL of 7 M in methanol, 35 mmol) wasstirred at room temperature for 16 hours. SPM32 silica metal scavenger(150 mg) was added and the reaction was stirred for 15 minutes. Themixture was filtered and the filtrate was concentrated in vacuo. Silicagel chromatography (0-100% ethyl acetate/petroleum ether) provided4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(54.5 mg, 31%) as a white solid. ESI-MS m/z calc. 547.10, found 548.1(M+1)+; 546.0 (M−1)−; retention time (Method E): 3.32 minutes (5 minuterun). ¹H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.49-8.48 (m, 2H), 8.06(d, J=2.9 Hz, 1H), 7.81 (t, J=8.6 Hz, 1H), 7.61-7.60 (m, 1H), 7.39 (d,J=8.8 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.09-7.06 (m, 1H), 6.66 (d, J=8.9Hz, 1H), 3.82 (s, 3H), 2.33 (s, 3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d6) δ−56.85, −59.11 (d, J=12.2 Hz), −117.84 (q, J=12.5 Hz) ppm.

Example 355-Chloro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(152)

Step 1:N-(2,5-Dichloro-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide

NaH (90 mg, 2.3 mmol) was added to 2,5-dichloropyridin-4-amine (125 mg,0.767 mmol) in DMF (1.5 mL) at 0° C. and was stirred for 10 minutes. Asolution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (prepared as described in Example 2, Step 4, 365 mg, 0.844mmol) in DMF (1.5 mL) was then added dropwise and warmed to roomtemperature and stirred for 16 hours. The reaction was quenched withsaturated aqueous NH₄Cl and diluted with ethyl acetate. The organiclayer was separated and washed with brine (3×), dried over MgSO₄,filtered and concentrated in vacuo to afford a light brown oil. Silicagel chromatography (0-40% ethyl acetate/petroleum ether) affordedN-(2,5-dichloro-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(190 mg, 44%). ESI-MS m/z calc. 558.00, found 558.8 (M+1)+; 556.8(M−1)−; retention time (Method F): 1.18 minutes (1.5 minute run).

Step 2: Methyl5-chloro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A mixture ofN-(2,5-dichloro-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(190.0 mg, 0.3398 mmol), Pd(dppf)Cl₂.DCM (27 mg, 0.033 mmol) andtriethylamine (100 μL, 0.718 mmol) in DMF (2.2 mL)/methanol (1.1 mL) wasbubbled with excess carbon monoxide in a pressure vessel. The vessel wassealed and heated to 80° C. for 24 hours. The reaction mixture wasfiltered, concentrated in vacuo and the crude methyl5-chloro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylatewas used directly in the next step. ESI-MS m/z calc. 582.81, found 583.2(M+1)+; retention time (Method F): 1.10 minutes (1.5 minute run).

Step 3:5-Chloro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(152)

A solution of crude methyl5-chloro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(198.0 mg, 0.3398 mmol) from Step 2 in ammonia (2.5 mL of 7 M inmethanol, 17.5 mmol) was stirred at room temperature for 24 hours. Thereaction mixture was reduced in volume in vacuo, filtered (0.45 μM PTFEsyringe filter) and purified by HPLC (10-95% acetonitrile/0.05% TFA) toprovide5-chloro-4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(103 mg, 53%). ESI-MS m/z calc. 567.04, found 568.2 (M+1)+; 566.1(M−1)−; retention time (Method E): 3.62 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.77 (s, 1H), 8.70 (s, 1H), 8.14 (d,J=2.5 Hz, 1H), 7.87-7.71 (m, 2H), 7.39 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.7Hz, 1H), 7.05 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H),3.80 (s, 3H) ppm.

Example 364-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxamide(207)

Step 1: Methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxylate

To a solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 2, Step 3, 150 mg, 0.362 mmol) indichloromethane (2 mL) at 0° C. was added DMF (3 μL, 0.04 mmol) andoxalyl chloride (95 μL, 1.09 mmol) dropwise. The reaction was stirredfor 2 hours then concentrated in vacuo to afford the acid chloride as apale yellow oil. The oil was dissolved in dichloromethane (2 mL) andadded dropwise to a stirring solution of methyl4-aminopyrimidine-2-carboxylate (61 mg, 0.40 mmol) and triethylamine(300 μL, 2.15 mmol) in dichloromethane at 0° C. (3 mL). The resultingmixture was allowed to warm to room temperature and stirred for 16hours. The reaction was concentrated in vacuo and purified by HPLC(37-100% acetonitrile/0.1% ammonium hydroxide) to provide methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxylate(10 mg, 5%). ESI-MS m/z calc. 549.08, found 550.0 (M+1)+; 547.9 (M−1)−;retention time (Method F): 1.04 minutes (1.5 minute run). ¹H NMR (400MHz, CD₃OD) δ 8.86 (dd, J=5.7, 1.8 Hz, 1H), 8.48 (s, 1H), 7.72 (t, J=8.4Hz, 1H), 7.33 (dd, J=8.9, 1.9 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 7.01-6.93(m, 1H), 6.68 (d, J=8.8 Hz, 1H), 4.00 (d, J=1.8 Hz, 3H), 3.84 (d, J=1.8Hz, 4H) ppm.

Step 2:4-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxamide(207)

Methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxylate(15 mg, 0.027 mmol) was dissolved in ammonia (1 mL of 7 M in methanol, 7mmol) and stirred at room temperature for 3 hours. The reaction mixturewas concentrated in vacuo, dissolved in DMSO, and purified by HPLC(37-100% acetonitrile/0.1% ammonium hydroxide) to provide4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxamide(3.8 mg, 26%) as a white solid. ESI-MS m/z calc. 534.08, found 534.96(M+1)+; 532.86 (M−1)−; retention time (Method E): 3.18 minutes (5 minuterun). ¹H NMR (400 MHz, MeOD) δ 8.74 (dd, J=5.8, 2.7 Hz, 1H), 8.32 (d,J=5.5 Hz, 1H), 7.60 (td, J=8.6, 2.6 Hz, 1H), 7.21 (dd, J=8.8, 2.7 Hz,1H), 6.99 (d, J=2.8 Hz, 1H), 6.85 (ddt, J=9.2, 3.0, 1.5 Hz, 1H), 6.56(dd, J=8.9, 2.5 Hz, 1H), 3.71 (d, J=2.6 Hz, 3H) ppm.

Example 376-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(169)

Step 1: Methyl6-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To a solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 2, Step 3, 100 mg, 0.241 mmol) indichloromethane (2 mL) at 0° C. was added DMF (10 μL, 0.13 mmol) andoxalyl chloride (70 μL, 0.8024 mmol) dropwise. The reaction mixture wasstirred for 2 hours then concentrated in vacuo to afford the acidchloride as a pale yellow oil. The oil was dissolved in dichloromethane(2 mL) and added dropwise to a solution of methyl6-aminopyridine-2-carboxylate (37 mg, 0.24 mmol) and triethylamine (210μL, 1.51 mmol) in dichloromethane (2 mL) at 0° C. The resulting mixturewas allowed to warm to room temperature and stirred for 16 hours. Thereaction mixture was concentrated in vacuo and purified by silica gelchromatography (0-50% ethyl acetate/petroleum ether) to provide methyl6-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(40 mg, 30%). ESI-MS m/z calc. 548.08, found 549.0 (M+1)+; 547.0 (M−1)−;retention time (Method F): 1.1 minutes (1.5 minute run). ¹H NMR (400MHz, CDCl₃) δ 9.16 (s, 1H), 8.63 (dd, J=7.1, 2.2 Hz, 1H), 7.98-7.88 (m,2H), 7.60-7.51 (m, 1H), 7.29-7.22 (m, 1H), 6.95-6.85 (m, 2H), 6.59 (d,J=9.0 Hz, 1H), 3.97 (d, J=12.0 Hz, 6H) ppm.

Step 2:6-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(169)

Methyl6-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(40 mg, 0.073 mmol) was dissolved in ammonia (2 mL of 7 M in methanol,14 mmol) and stirred at 45° C. temperature in a sealed tube for 16hours. The reaction was concentrated in vacuo, dissolved in DMSO (1 mL)and purified by HPLC (29-100% acetonitrile/0.1% ammonium hydroxide) toprovide6-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(9 mg, 22%) as an off-white solid. ESI-MS m/z calc. 533.08, found 534.31(M+1)+; retention time (Method E): 3.32 minutes (5 minute run). ¹H NMR(400 MHz, CD₃OD) δ 8.48 (d, J=8.3 Hz, 1H), 8.03 (t, J=7.9 Hz, 1H), 7.92(dd, J=7.6, 0.9 Hz, 1H), 7.70 (t, J=8.5 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H),7.10 (d, J=2.6 Hz, 1H), 6.96 (ddd, J=8.9, 2.8, 1.3 Hz, 1H), 6.67 (d,J=8.9 Hz, 1H), 3.82 (s, 3H), 3.33 (p, J=1.6 Hz, 2H) ppm.

Example 384-[[3-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(189)

Step 1:N-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide

To a solution of3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(prepared as described in Example 5, Step 2, 300 mg, 0.788 mmol) indichloromethane (5 mL) at 0° C. was added DMF (7 μL, 0.08 mmol) andoxalyl chloride (235 μL, 2.69 mmol) dropwise. The reaction was allowedto warm to room temperature over 3 hours and then concentrated in vacuo.The residue was dissolved in dichloromethane (5 mL), cooled to 0° C. andtreated with 2-bromo-5-methyl-pyridin-4-amine (221 mg, 1.18 mmol)followed by triethylamine (980 μL, 7.03 mmol). The resulting mixture wasstirred and warmed to ambient temperature over 16 hours. The reactionmixture was diluted with water (10 mL) and extracted withdichloromethane (2×10 mL). The combined organics were dried over MgSO₄,filtered and concentrated in vacuo. Silica gel chromatography (0-60%ethyl acetate/petroleum ether) providedN-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(140 mg, 32%). ESI-MS m/z calc. 547.98, found 551.0 (M+1)+; retentiontime (Method F): 1.12 minutes (1.5 minute run).

Step 2: Methyl4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

N-(2-Bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(140 mg, 0.255 mmol) was dissolved in methanol (2.5 mL) andtriethylamine (81 μL, 0.58 mmol), and Pd(dppf)Cl₂.DCM (43 mg, 0.053mmol) was added. Carbon monoxide was bubbled through the vigorouslystirring reaction mixture for 5 minutes. The reaction mixture was thenheated at 75° C. under carbon monoxide atmosphere for 16 hours. Thereaction was cooled to room temperature, filtered through a pad ofCelite eluting with methanol and concentrated in vacuo. Silica gelchromatography (30-80% ethyl acetate/petroleum ether) provided methyl4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(100 mg, 74%). ESI-MS m/z calc. 528.07, found 529.0 (M+1)+; retentiontime (Method F): 1.02 minutes (0.5 minute run).

Step 3:4-[[3-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(189)

Methyl4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(100 mg, 0.189 mmol) and ammonia (3 mL of 7 M, 21 mmol) were stirred atroom temperature under N₂ atmosphere for 16 hours. Additional ammonia (3mL of 7 M in methanol, 21 mmol) was added and the reaction was stirredfor 24 hours. The reaction mixture was concentrated in vacuo andpurified by silica gel chromatography (0-100% ethyl acetate/petroleumether) to provide4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(34 mg, 35%) as a white solid. ESI-MS m/z calc. 513.07, found 514.0(M+1)+; retention time: 3.33 minutes (5 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 10.50 (s, 1H), 8.47 (s, 2H), 8.09-8.04 (m, 1H), 7.67-7.58 (m,2H), 7.30 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.8 Hz, 1H), 7.06-6.98 (m, 1H),6.62 (d, J=9.0 Hz, 1H), 3.81 (s, 3H), 2.31 (s, 3H) ppm.

Example 39N-(5-Carbamoyl-2-deuterio-4-fluoro-phenyl)-2-fluoro-6-[2,3,6-trideuterio-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(213)

Step 1: 2,3,6-Tribromo-4-(trifluoromethoxy)phenol

A stirring mixture of 4-(trifluoromethoxy)phenol (2.0 g, 11 mmol) and Fe(44 mg, 0.79 mmol) in CHCl₃ (20 mL) was slowly treated with Br₂ (2.3 mL,44.64 mmol) (exothermic, strong gas evolution). The deep red mixture wasstirred for 16 hours at room temperature. The mixture was diluted withdichloromethane and water, and treated with solid sodium bisulfite untilthe color had changed from orange to almost colorless. The phases wereseparated and the organic phase was washed twice with water. The aqueousphase was extracted with dichloromethane and the combined organic phaseswere dried over MgSO₄, filtered and concentrated in vacuo. The solid wascrystallized from heptane to provide2,3,6-tribromo-4-(trifluoromethoxy)phenol (3.3 g, 70%). ¹H NMR (400 MHz,DMSO-d6) δ 10.80 (s, 1H), 7.86 (q, J=1.1 Hz, 1H) ppm.

Step 2: 2,3,6-Trideuterio-4-(trifluoromethoxy)phenol

2,3,6-Tribromo-4-(trifluoromethoxy)phenol (250 mg, 0.603 mmol) was addedto a round bottom flask and evaporated with methanol-d4 (3×3 mL). Theflask was charged with dry 10% Pd/C (130 mg, 0.061 mmol) under N₂atmosphere, followed by methanol-d4 (5 mL) and triethylamine (336 μL,2.411 mmol). The flask was flushed with deuterium gas and the reactionwas stirred vigorously under deuterium atmosphere for 90 minutes. Thereaction mixture was filtered (fritted funnel, followed 0.4 micronsyringe filter) then diluted with diethyl ether and washed with 0.5 MHCl (2×5 mL) and brine. The ether layer was dried over MgSO₄, filtered,and carefully concentrated in vacuo to provide2,3,6-trideuterio-4-(trifluoromethoxy)phenol (109 mg, 100%). ¹H NMR (400MHz, DMSO-d6) δ 9.75 (s, 1H), 7.19-7.10 (m, 1H) ppm.

Step 3:2-Fluoro-6-[2,3,6-trideuterio-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicAcid

6-Bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (3.27 g, 11.4 mmol) ina 100-mL round bottom flask was evaporated sequentially with methanol-d4(4×2 mL) and benzene-d6 (2 mL). Anhydrous cesium carbonate (4.0 g, 12mmol) was added and the mixture was stored under high vacuum for 16hours. The flask was repressurized under N₂, and a solution of2,3,6-trideuterio-4-(trifluoromethoxy)phenol (2.07 g, 11.4 mmol) inbenzene-d6 (50 mL) was added. The solution was bubbled with N₂ for 10minutes then treated with copper (I) iodide (415 mg, 2.18 mmol). Theflask was flushed with N₂ and heated at 75° C. for 2.5 hours. Thereaction mixture was cooled to room temperature then diluted with D20(˜10 mL). The mixture was stirred for 10 minutes, then further dilutedwith ether and acidified with cold 1 M HCl. The ether layer wasseparated, washed with brine, dried over MgSO₄, filtered andconcentrated. Purification using silica gel chromatography (0-5%methanol/dichloromethane) followed by trituration of the resulting solidwith hexanes provide2-fluoro-6-[2,3,6-trideuterio-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (3.20 g, 73%) as a white solid. ESI-MS m/z calc. 387.04, found388.1 (M+1)+; retention time (Method A): 0.72 minutes (1 minute run). ¹HNMR (400 MHz, DMSO-d6) δ 14.15 (br s, 1H), 7.84 (t, J=8.7 Hz, 1H), 7.47(d, J=0.9 Hz, 1H), 6.98-6.88 (m, 1H) ppm.

Step 4:N-(5-Carbamoyl-2-deuterio-4-fluoro-phenyl)-2-fluoro-6-[2,3,6-trideuterio-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(213)

A solution of2-fluoro-6-[2,3,6-trideuterio-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (2.00 g, 5.17 mmol), 5-amino-4-deuterio-2-fluoro-benzamide(prepared as described in Preparation 5, 0.801 g, 5.16 mmol) andtriethylamine (1.44 mL, 10.33 mmol) in NMP (20 mL) was treated with HATU(2.16 g, 5.68 mmol) and stirred at room temperature for 16 hours. Thereaction mixture was partitioned between ethyl acetate (100 mL) andwater (300 mL) and the layers separated. The organic layer was washedwith 0.5 M citric acid, saturated sodium carbonate/water (1:1) andbrine. The aqueous phases were back-extracted once with ethyl acetateand the combined organic phases were dried over MgSO₄, filtered andconcentrated in vacuo. The crude was dissolved in ethyl acetate,filtered (0.45 μm syringe filter) and evaporated to provide a paleyellow foam. The foam was dissolved in dichloromethane (10-20 mL) andstirred at room temperature for 1 hour to give a colorless suspension.The solid was collected by filtration, washed with cold dichloromethaneand dried under vacuum at 40-45° C. to provideN-(5-carbamoyl-2-deuterio-4-fluoro-phenyl)-2-fluoro-6-[2,3,6-trideuterio-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(2.4 g, 88%) as an off-white solid. ESI-MS m/z calc. 524.09, found 525.1(M+1)+; retention time (Method B): 1.82 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.95 (d, J=6.4 Hz, 1H), 7.86 (t,J=8.6 Hz, 1H), 7.70 (d, J=16.3 Hz, 2H), 7.48 (s, 1H), 7.28 (d, J=10.1Hz, 1H), 6.90 (d, J=8.8 Hz, 1H) ppm.

Example 404-[[2-Fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(110)

To a stirring solution of4-[[2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(48, 521 mg, 1.04 mmol) in anhydrous dichloromethane (5 mL) at 0° C.under N₂ atmosphere was added 3-chloroperoxybenzoic acid (790 mg, 3.53mmol). The reaction was allowed to warm to room temperature and stirredfor 4 hours. The reaction was cooled to 0° C. and additional3-chloroperoxybenzoic acid (348 mg, 1.56 mmol) was added. The reactionwas warmed to room temperature for an additional 2.5 hours, thenfiltered and concentrated in vacuo. Silica gel chromatography (0-100%ethyl acetate/hexanes) provided4-[[2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(358 mg, 67%) as a white solid. ESI-MS m/z calc. 519.07, found 520.0(M+1)+; retention time (Method B): 1.65 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.58 (d, J=4.6 Hz, 1H), 8.51 (d,J=3.2 Hz, 1H), 8.37 (d, J=7.1 Hz, 1H), 8.29 (d, J=4.7 Hz, 1H), 7.90 (t,J=8.7 Hz, 1H), 7.84 (dd, J=7.1, 3.3 Hz, 1H), 7.55-7.43 (m, 2H),7.41-7.30 (m, 2H), 6.92 (d, J=8.9 Hz, 1H) ppm.

Example 41N-(5-Carbamoyl-4-fluoro-2-methyl-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(124)

Step 1:N-(5-Carbamoyl-4-fluoro-2-methyl-phenyl)-2,6-difluoro-3-(trifluoromethyl)benzamide

To a solution of 2,6-difluoro-3-(trifluoromethyl)benzoic acid (200 mg,0.885 mmol) in dichloromethane (5 mL) at 0° C. was added DMF (40 μL,0.52 mmol) and oxalyl chloride (230 μL, 2.64 mmol) dropwise. Thereaction was allowed to warm to room temperature and stirred for 1 hour.The reaction mixture was concentrated in vacuo to afford a yellow solid.The solid was dissolved in dichloromethane (2 mL) and treated with5-amino-2-fluoro-4-methyl-benzamide (150 mg, 0.892 mmol) andtriethylamine (250 μL, 1.79 mmol). The reaction mixture was stirred atroom temperature for 45 minutes, then washed with water (10 mL) andbrine (2 mL), dried over MgSO₄, filtered and concentrated in vacuo.Silica gel chromatography (0-100% ethyl acetate/petroleum ether)providedN-(5-carbamoyl-4-fluoro-2-methyl-phenyl)-2,6-difluoro-3-(trifluoromethyl)benzamide(120 mg, 36%). ESI-MS m/z calc. 376.07, found 377.0 (M+1)+; retentiontime (Method F): 0.77 minutes (1.5 minute run).

Step 2:N-(5-Carbamoyl-4-fluoro-2-methyl-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(124)

N-(5-Carbamoyl-4-fluoro-2-methyl-phenyl)-2,6-difluoro-3-(trifluoromethyl)benzamide(88 mg, 0.23 mmol), 4-(trifluoromethoxy)phenol (70 mg, 0.39 mmol) andCs₂CO₃ (100 mg, 0.307 mmol) were combined in acetonitrile (1 mL) and themixture was stirred for 16 hours. The reaction mixture was partitionedbetween ethyl acetate and water and the layers separated. The aqueouslayer was further extracted with ethyl acetate and the combined organicswere washed with brine, dried over MgSO₄, and concentrated in vacuo.Silica gel chromatography (0-100% ethyl acetate/petroleum ether)providedN-(5-carbamoyl-4-fluoro-2-methyl-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(41 mg, 32%) as a white solid. ESI-MS m/z calc. 534.08, found 535.0(M+1)+; retention time (Method E): 3.3 minutes (5 minute run). ¹H NMR(500 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.87 (t, J=8.6 Hz, 1H), 7.70 (d,J=7.1 Hz, 1H), 7.63 (d, J=15.0 Hz, 2H), 7.55-7.44 (m, 2H), 7.40-7.33 (m,2H), 7.26-7.20 (m, 1H), 6.92 (d, J=8.8 Hz, 1H), 2.24 (s, 3H) ppm.

Example 424-[[5-Fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(75)

Step 1: Methyl4-[[2,5-difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To a solution of 2,5-difluoro-4-(trifluoromethyl)benzoic acid (200 mg,0.885 mmol) in dichloromethane (4 mL) at 0° C. was added DMF (7 μL, 0.1mmol) and oxalyl chloride (265 μL, 3.04 mmol) dropwise. The reaction wasallowed to warm to room temperature and stirred for 3 hours. Thereaction mixture was concentrated in vacuo, dissolved in dichloromethane(3 mL) and cooled to 0° C. Methyl 4-aminopyridine-2-carboxylate (185 mg,1.22 mmol) was added followed by triethylamine (652 μL, 4.68 mmol) andthe resulting mixture was allowed to warm to room temperature andstirred for 16 hours. The reaction mixture was diluted with water (10mL) and extracted with dichloromethane (2×10 mL). The combined organicswere dried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-60% ethyl acetate/petroleum ether) provided methyl4-[[2,5-difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(217 mg, 68%). ESI-MS m/z calc. 360.05, found 361.0 (M+1)+; retentiontime (Method F): 0.78 minutes (1.5 minute run).

Step 2: Methyl4-[[5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

Methyl4-[[2,5-difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(215 mg, 0.597 mmol), Cs₂CO₃ (292 mg, 0.896 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (149 mg, 0.716 mmol) were heated inacetonitrile (5 mL) at 75° C. under N₂ atmosphere for 10 hours. Thereaction mixture was cooled and partitioned between ethyl acetate andwater. The layers were separated and the aqueous layer was extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried over MgSO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (0-50% ethyl acetate/petroleumether) provided methyl4-[[5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(143 mg, 44%) as a white solid. ESI-MS m/z calc. 548.08, found 549.0(M+1)+; retention time (Method F): 1.02 minutes (1.5 minute run).

Step 3:4-[[5-Fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(75)

A solution of methyl4-[[5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(143 mg, 0.2608 mmol) in ammonia (4 mL of 7 M in methanol, 28 mmol) wasstirred for 16 hours under N₂ atmosphere. The reaction mixture wasfiltered to provide4-[[5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(106 mg, 75%) as a white solid. ESI-MS m/z calc. 533.08, found 534.0(M+1)+; retention time (Method E): 3.55 minutes (5 minute run). ¹H NMR(500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.29 (d,J=2.1 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J=10.0 Hz, 1H), 7.84-7.76 (m, 1H),7.71-7.55 (m, 1H), 7.32-7.08 (m, 3H), 6.97 (ddd, J=8.8, 2.7, 1.2 Hz,1H), 3.75 (s, 3H) ppm.

Example 434-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]-5-methyl-pyridine-2-carboxamide(211)

Step 1: Methyl 4-chloro-2,6-difluoro-benzoate

Methyl iodide (1.3 mL, 20.9 mmol) was added to a stirred suspension of4-chloro-2,6-difluoro-benzoic acid (4.0 g, 20.8 mmol) and Cs₂CO₃ (3.4 g,10.44 mmol) in DMF (40 mL), and the reaction mixture was stirred atambient temperature for 16.5 hours. The reaction mixture was added towater (150 mL) with stirring and the resulting precipitate was filteredand dried to provide methyl 4-chloro-2,6-difluoro-benzoate (3.7 g, 86%)as a white solid. ¹H NMR (500 MHz, DMSO-d6) δ 7.59-7.58 (m, 1H),7.56-7.55 (m, 1H), 3.90 (s, 3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ−109.07 ppm.

Step 2: Methyl4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A mixture of Cs₂CO₃ (690 mg, 2.12 mmol),2-methoxy-4-(trifluoromethoxy)phenol (305 mg, 1.47 mmol) and methyl4-chloro-2,6-difluoro-benzoate (288 mg, 1.39 mmol) in DMF (5 mL) wasstirred at ambient temperature for 22.5 hours. The reaction was dilutedwith ethyl acetate and washed with water (3×) and brine. The organiclayer was dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (0-10% ethylacetate/petroleum ether) to provide methyl4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (468mg, 85%) as a colorless oil. ESI-MS m/z calc. 394.02, found 395.1(M+1)+; retention time (Method F): 1.13 minutes (1.5 minute run). ¹H NMR(400 MHz, CDCl₃) δ 7.12-7.09 (m, 1H), 6.89-6.85 (m, 3H), 6.47 (t, J=1.6Hz, 1H), 3.93 (s, 3H), 3.83 (s, 3H) ppm. ¹⁹F NMR (376 MHz, CDCl₃) δ−58.01, −111.00 ppm.

Step 3: methyl4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoate

n-Butyllithium (565 μL of 2.5 M, 1.412 mmol) was added to a stirredsolution of diisopropylamine (185 μL, 1.320 mmol) in THF (5 mL) at −78°C. and the reaction warmed to 0° C. and stirred for 20 minutes. The LDAformed was added dropwise to a solution of methyl4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (465mg, 1.18 mmol) in THF (5 mL) at −78° C. The reaction was stirred at thistemperature for 10 minutes then methyl iodide (110 μL, 1.77 mmol) wasadded. The mixture was stirred at −78° C. for 30 minutes then allowed towarm to room temperature. The reaction was quenched by the addition ofwater and the mixture was extracted with ethyl acetate (3×). Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (0-10% ethyl acetate/petroleum ether) to provide methyl4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoate(393 mg, 82%) as a colorless oil. ESI-MS m/z calc. 408.04, found 409.1(M+1)+; retention time (Method F): 1.17 minutes (1.5 minute run). ¹H NMR(400 MHz, CDCl₃) δ 7.06 (d, J=8.6 Hz, 1H), 6.87-6.82 (m, 2H), 6.55 (d,J=1.8 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.28 (d, J=2.4 Hz, 3H) ppm.¹⁹F NMR (376 MHz, CDCl₃) δ −58.03, −112.16 ppm.

Step 4:4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicAcid

To a slurry of methyl4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoate(390 mg, 0.954 mmol) in methanol (10 mL) and water (10 mL) was addedNaOH (380 mg, 9.50 mmol). The reaction mixture was stirred at roomtemperature for 19 hours then the temperature increased to 50° C. for 24hours. The reaction was cooled to room temperature and concentrated. Theresidue was taken up in water and acidified with 1M HCl. The mixture wasextracted with ethyl acetate (3×) and the combined organic extracts weredried over MgSO₄, filtered and concentrated in vacuo to provide4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid (363 mg, 96%) as a white solid. ESI-MS m/z calc. 394.02, found393.1 (M−1)−; retention time (Method F): 0.74 minutes (1.5 minute run).¹H NMR (400 MHz, CDCl₃) δ 7.20-7.17 (m, 1H), 6.93-6.90 (m, 2H), 6.58 (d,J=1.7 Hz, 1H), 3.85 (s, 3H), 2.30 (d, J=2.5 Hz, 3H) ppm. ¹⁹F NMR (376MHz, CDCl₃) δ −58.00, −109.07 ppm.

Step 5:N-(2-Bromo-5-methyl-4-pyridyl)-4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzamide

To a stirring solution of4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid (280 mg, 0.709 mmol) in dichloromethane (10 mL) at 0° C. was addedDMF (5 μL, 0.06 mmol) and oxalyl chloride (190 μL, 2.18 mmol) dropwise.The reaction mixture was allowed to warm to room temperature over 3.5hours then concentrated in vacuo. The residue was dissolved indichloromethane (10 mL) and added dropwise to a solution of2-bromo-5-methyl-pyridin-4-amine (160 mg, 0.855 mmol) and TEA (500 μL,3.59 mmol) in dichloromethane (10 mL) at 0° C. The resulting mixture wasallowed to warm to room temperature and stirred for 18 hours. Thereaction mixture was quenched with water and the layers separated. Theaqueous layer was extracted with dichloromethane and the combinedorganics extracts were dried over MgSO₄, filtered and concentrated invacuo. Silica gel chromatography (0-50% ethyl acetate/petroleum ether)providedN-(2-bromo-5-methyl-4-pyridyl)-4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzamide(150 mg, 37%) as a white solid. ESI-MS m/z calc. 561.99, found 565.1(M+1)+; 563.0 (M−1)−; retention time (Method F): 1.13 minutes (1.5minute run). ¹H NMR (500 MHz, CDCl₃) δ 8.62 (s, 1H), 8.30 (s, 1H), 8.12(s, 1H), 7.19 (d, J=8.7 Hz, 1H), 6.96-6.92 (m, 2H), 6.51 (d, J=1.7 Hz,1H), 3.82 (s, 3H), 2.32 (d, J=2.5 Hz, 3H), 2.14 (s, 3H) ppm. ¹⁹F NMR(471 MHz, CDCl₃) δ −57.97, −110.38 ppm.

Step 6: Methyl4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzamide(149 mg, 0.264 mmol) was dissolved in methanol, (8 mL) and triethylamine(75 μL, 0.54 mmol) and Pd(dppf)Cl₂.DCM (45 mg, 0.055 mmol) were added.Carbon monoxide was bubbled through the vigorously stirred reactionmixture for 5 minutes. The reaction mixture was sealed and heated at 75°C. for 16 hours. The mixture was cooled to room temperature and passedthrough a pad of Celite. The Celite was rinsed with methanol and thefiltrate concentrated in vacuo. Silica gel chromatography (0-100% ethylacetate/petroleum ether) provided methyl4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]-5-methyl-pyridine-2-carboxylate(105 mg, 73%) as a red solid. ESI-MS m/z calc. 542.09, found 543.3(M+1)+; 541.2 (M−1)−; retention time (Method F): 1.02 minutes (1.5minute run). ¹H NMR (500 MHz, CDCl₃) δ 9.08 (s, 1H), 8.51 (s, 1H), 8.34(s, 1H), 7.20 (d, J=8.6 Hz, 1H), 6.96-6.90 (m, 2H), 6.53 (d, J=1.6 Hz,1H), 4.02 (s, 3H), 3.83 (s, 3H), 2.33 (d, J=2.4 Hz, 3H), 2.26 (s, 3H)ppm. ¹⁹F NMR (471 MHz, CDCl₃) δ −57.98, −110.38 ppm.

Step 7:4-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]-5-methyl-pyridine-2-carboxamide(211)

A mixture of methyl4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]-5-methyl-pyridine-2-carboxylate(105 mg, 0.193 mmol) and ammonia (3 mL of 7 M in methanol, 21.00 mmol)was stirred at room temperature for 20 hours. An additional portion of7M ammonia (3 mL of 7 M in methanol, 21.00 mmol) was added and thereaction was stirred at ambient temperature for 23.5 hours. The reactionmixture was concentrated in vacuo. Silica gel chromatography (0-100%ethyl acetate/petroleum ether) followed by HPLC purification (0-100%acetonitrile/0.1% ammonium hydroxide) and lyophilization of productfractions provided4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]-5-methyl-pyridine-2-carboxamide(22 mg, 22%) as a white solid. ESI-MS m/z calc. 527.09, found 528.2(M+1)+; 526.2 (M−1)−; retention time (Method C): 3.53 minutes (5 minuterun). ¹H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.45 (s, 2H), 8.04-8.03(m, 1H), 7.58 (s, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H),7.02-7.00 (m, 1H), 6.67 (s, 1H), 3.81 (s, 3H), 2.28 (s, 6H) ppm. ¹⁹F NMR(471 MHz, DMSO-d6) δ −56.86, −114.46 ppm.

Example 444-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(201)

This compound was made in an analogous fashion to Example 43, exceptemploying 4-aminopyridine-2-carboxamide in the amide formation step(Step 5). The yield of the desired product after purification was 20 mg(19%). ESI-MS m/z calc. 513.07, found 513.9 (M+1)+; 511.7 (M−1)−;retention time (Method E): 3.32 minutes (5 minute run). ¹H NMR (500 MHz,DMSO-d6) δ 11.25 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.30 (d, J=1.9 Hz,1H), 8.08 (d, J=2.6 Hz, 1H), 7.81 (dd, J=5.4, 2.1 Hz, 1H), 7.64 (d,J=2.5 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.00-6.98(m, 1H), 6.73-6.65 (m, 1H), 3.78 (s, 3H), 2.27 (d, J=2.0 Hz, 3H) ppm;¹⁹F NMR (471 MHz, DMSO-d6) δ −56.89, −114.33 ppm.

Example 45N-(3-Carbamoyl-4-fluoro-phenyl)-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(92)

N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(Example 2, 54 mg, 0.098 mmol) and sodium methoxide (1 mL of 0.5 M inmethanol, 0.5 mmol) were stirred at 80° C. for 3 hours. The reactionmixture was concentrated in vacuo. HPLC purification (1-99%acetonitrile/water) providedN-(3-carbamoyl-4-fluoro-phenyl)-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(27 mg, 49%). ESI-MS m/z calc. 562.10, found 563.0 (M+1)+; retentiontime (Method B): 1.82 minutes (3 min run). ¹H NMR (400 MHz, DMSO-d6) δ10.88 (s, 1H), 8.03 (dd, J=6.4, 2.8 Hz, 1H), 7.82-7.77 (m, 1H), 7.71 (d,J=17.3 Hz, 2H), 7.66 (d, J=8.9 Hz, 1H), 7.38-7.19 (m, 3H), 7.08-6.98 (m,1H), 6.51 (d, J=8.8 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 3H) ppm.

Example 465-[[2-Methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(202)

This compound was made in an analogous fashion to Example 45 from 193.The yield of the desired product after HPLC purification was 22 mg(36%). ESI-MS m/z calc. 545.10, found 546.1 (M+1)+; 544.0 (M−1)−;retention time: 3.29 minutes (Method E). ¹H NMR (500 MHz, DMSO-d6) δ11.20 (s, 1H), 8.88 (s, 1H), 8.31 (dd, J=8.7, 2.4 Hz, 1H), 8.04 (d,J=8.5 Hz, 1H), 8.01-7.97 (m, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.55-7.51 (m,1H), 7.31 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.02 (ddd, J=8.8,2.7, 1.3 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H)ppm.

Example 475-Fluoro-4-(2-methoxy-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamido)picolinamide(128)

Compound 128 was prepared according to the experimental described abovein Example 33.

Example 486-[[2-Methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide(205)

Step 1: Methyl6-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxylate

To an ice-cooled solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (100 mg, 0.241 mmol) in dichloromethane (2 mL) was added DMF (10μL, 0.13 mmol) and oxalyl chloride (70 μL, 0.8024 mmol) dropwise. Thereaction mixture was stirred for 2 hours then concentrated in vacuo toafford the acid chloride as a pale yellow oil. The product was dissolvedin dichloromethane (2 mL) and added dropwise to a solution of methyl6-aminopyridine-3-carboxylate (33 mg, 0.22 mmol) and TEA (210 μL, 1.507mmol) in dichloromethane (3 mL) at 0° C. The mixture was allowed to warmto room temperature and stirred for 16 hours. The reaction mixture wasconcentrated in vacuo and purified by silica gel chromatography (0-100%ethyl acetate/petroleum ether) to afford methyl6-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxylate(15 mg, 11%) as an off-white waxy solid. ESI-MS m/z calc. 548.08, found549.0 (M+1)+; retention time (Method F): 1.11 minutes (1.5 minute run).¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.87 (dd, J=2.3, 0.8 Hz, 1H),8.52-8.45 (m, 1H), 8.37 (ddd, J=8.3, 4.8, 2.3 Hz, 1H), 7.62-7.52 (m,1H), 7.41 (t, J=8.3 Hz, 1H), 7.28-7.20 (m, 1H), 7.24-7.09 (m, 1H),6.96-6.86 (m, 3H), 6.88-6.81 (m, 2H), 6.58 (d, J=8.9 Hz, 1H), 6.36 (d,J=8.9 Hz, 1H), 3.74 (s, 2H), 1.38-1.21 (m, 3H) ppm.

Step 2:6-[[2-Methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide(205)

Methyl6-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxylate(15 mg, 0.027 mmol) was dissolved in ammonia (2 mL of 7 M in methanol,14 mmol) in a sealed tube and stirred at 45° C. for 16 hours. Additionalammonia was added (1 mL of 7 M in methanol, 7 mmol) and the mixture washeated for an additional 48 hours. The reaction mixture was concentratedin vacuo and purified by HPLC (37-100% acetonitrile/0.1% ammoniumhydroxide) to provide6-[[2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide(0.4 mg, 2%). ESI-MS m/z calc. 545.10, found 545.96 (M+1)+; 543.96(M−1)−; retention time (Method E): 3.24 minutes (5 minute run). ¹H NMR(400 MHz, CD₃OD) δ 8.85 (s, 1H), 8.49-8.24 (m, 2H), 7.62 (d, J=8.9 Hz,1H), 7.29 (d, J=8.8 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J=9.4 Hz, 1H), 6.55(d, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.83 (s, 3H) ppm.

Example 492-Fluoro-5-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-4-methyl-benzamide(139)

Step 1: Methyl2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate

To a solution of methyl 2,6-difluoro-4-(trifluoromethyl)benzoate (1.173g, 4.885 mmol) in DMF (15 mL), was added2-methoxy-4-(trifluoromethoxy)phenol (1.017 g, 4.886 mmol) and Cs₂CO₃(4.816 g, 14.78 mmol) and the mixture was heated at 80° C. for 1 hour.The reaction was cooled and diluted with ethyl acetate and saturatedaqueous sodium chloride solution and the layers were separated. Theorganic layer was washed with additional sodium chloride solution, driedover MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-5% ethyl acetate/hexanes) provided methyl2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate(2.168 g, 104%) containing 0.3 equivalents of DMF by NMR. ESI-MS m/zcalc. 428.05, found 429.0 (M+1)+; retention time (Method F): 1.14minutes (1.5 minute run).

Step 2:2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicAcid

To a flask charged with methyl2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate(5.71 g, 13.3 mmol) in THF (60 mL) was added aqueous NaOH (58 mL of 2 M,116 mmol). The reaction mixture was stirred for 1 hour at roomtemperature then refluxed for 16 hours. The solvent was evaporated andthe residue was cooled to 0° C., acidified with 2 M HCl and extractedwith dichloromethane (3×). The organic layer was dried over MgSO₄,filtered and concentrated to provide2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (5.3 g, 96%) as a white solid. ESI-MS m/z calc. 414.03, found 412.9(M−1)−; retention time (Method F): 0.73 minutes (1.5 minute run). ¹H NMR(400 MHz, CDCl₃) δ 7.12-7.08 (m, 1H), 7.08-7.03 (m, 1H), 6.82 (m, 2H),6.63 (s, 1H), 3.73 (s, 3H) ppm. ¹⁹F NMR (376 MHz, CDCl₃) δ −58.44,−63.89, −108.83 (d, J=9.0 Hz) ppm.

Step 3:2-Fluoro-5-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-4-methyl-benzamide(139)

To a solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (100 mg, 0.227 mmol) in dichloromethane (2 mL) at 0° C. was addedDMF (12 μL, 0.16 mmol) followed by careful addition of oxalyl chloride(36 μL, 0.41 mmol). The ice-bath was removed after 5 minutes and thereaction was allowed to warm to room temperature over 40 minutes. Thesolution was concentrated in vacuo and azeotroped with dichloromethane(2×) to provide2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzoylchloride. The residue was taken up in THF (1.8 mL) and cooled to 0° C.DIEA (123 μL, 0.706 mmol) was added followed by5-amino-2-fluoro-4-methyl-benzamide (prepared as described inPreparation 4, 40 mg, 0.24 mmol). The resulting solution was stirred at0° C. for 30 minutes and then at room temperature for 2 hours. HPLCpurification (0-100% acetonitrile/0.1% NH₃ in water) followed bylyophilization of product fractions provided2-fluoro-5-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-4-methyl-benzamide(45 mg, 35%) as a white solid. ESI-MS m/z calc. 564.09, found 565.0(M+1)+; retention time (Method E): 3.37 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.71-7.62(m, 3H), 7.32 (d, J=8.8 Hz, 1H), 7.31-7.20 (m, 2H), 7.05 (ddd, J=8.8,2.7, 1.3 Hz, 1H), 6.82 (1H, s), 3.83 (s, 3H), 2.27 (s, 3H) ppm. ¹⁹F NMR(376 MHz, DMSO-d6) δ −57.34, −62.02, −112.85 (d, J=8.6 Hz), −116.80 (td,J=9.7, 8.5, 4.6 Hz) ppm.

Example 50N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(140)

This compound was made in an analogous fashion to Example 49 from2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzoylchloride and 5-amino-2-fluoro-benzamide. The yield of the desiredproduct after HPLC purification was (70 mg, 56%). ESI-MS m/z calc.550.08, found 551.0 (M+1)+; retention time (Method E): 3.35 minutes (5minute run). ¹H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.99 (dd, J=6.4,2.8 Hz, 1H), 7.79-7.75 (m, 2H), 7.70 (s, 1H), 7.68-7.62 (m, 1H),7.35-7.26 (m, 2H), 7.24 (d, J=2.7 Hz, 1H), 7.03 (ddd, J=8.8, 2.7, 1.3Hz, 1H), 6.82 (d, J=1.4 Hz, 1H), 3.79 (s, 3H) ppm. ¹⁹F NMR (376 MHz,DMSO-d6) δ −57.35, −62.04, −112.69 (d, J=8.6 Hz), −119.00 (d, J=3.0 Hz)ppm.

Example 515-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(187)

This compound was made in an analogous fashion to Example 49 from2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzoylchloride and 5-aminopyridine-2-carboxamide. The yield of the desiredproduct after HPLC purification was (30 mg, 23%). ESI-MS m/z calc.533.08, found 534.0 (M+1)+; 531.8 (M−1)−; retention time (Method E):3.28 minutes (5 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H),8.85 (d, J=2.3 Hz, 1H), 8.27 (dd, J=8.6, 2.5 Hz, 1H), 8.10-8.00 (m, 2H),7.69 (d, J=8.6 Hz, 1H), 7.57 (s, 1H), 7.33 (d, J=8.9 Hz, 1H), 7.23 (d,J=2.8 Hz, 1H), 7.06-6.98 (m, 1H), 6.88 (s, 1H), 3.78 (s, 3H), 3.30 (s,17H) ppm.

Example 524-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(163)

Step 1: Methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To a solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (200 mg, 0.483 mmol) in dichloromethane (3.5 mL) at 0° C. was addedDMF (4 μL, 0.05 mmol) and oxalyl chloride (145 μL, 1.66 mmol) dropwise.The reaction was allowed to warm to room temperature over 3 hours. Thereaction mixture was concentrated in vacuo, dissolved in dichloromethane(3.5 mL) and cooled to 0° C. Methyl 4-aminopyridine-2-carboxylate (95mg, 0.62 mmol) was added followed by triethylamine (360 μL, 2.58 mmol).The resulting mixture was stirred and warmed to room temperature over 16hours. The reaction mixture was diluted with water (10 mL) and extractedwith dichloromethane (2×10 mL). The combined organics were dried overMgSO₄, filtered and concentrated in vacuo. Silica gel chromatography(30-70% ethyl acetate/petroleum ether) provided methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(129 mg, 49%). ESI-MS m/z calc. 548.08, found 549.0 (M+1)+; retentiontime: 1.04 minutes (1.5 min run).

Step 2:4-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(163)

A solution of methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(129 mg, 0.235 mmol) in ammonia (3.8 mL of 7 M in methanol, 26.6 mmol)was stirred at room temperature for 16 hours. The reaction mixture wasconcentrated in vacuo and purified by HPLC (37-100% acetonitrile/0.1%ammonium hydroxide) to provide4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(44 mg, 35%) as a white solid. ESI-MS m/z calc. 533.08, found 534.0(M+1)+; retention time (Method E): 3.42 minute (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.68-8.48 (m, 1H), 8.31 (d, J=2.1Hz, 1H), 8.11 (d, J=2.8 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.73-7.63(m, 2H), 7.33 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.8 Hz, 1H), 7.02 (ddd,J=8.8, 2.7, 1.3 Hz, 1H), 6.86 (d, J=1.4 Hz, 1H), 3.78 (s, 3H) ppm.

Example 534-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(153)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide

To a solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (1.80 g, 4.35 mmol) in dichloromethane (25 mL) was added DMF (36μL, 0.47 mmol) and oxalyl chloride (1.30 mL, 14.9 mmol) dropwise. Thereaction mixture was allowed to warm to room temperature over 3 hours.The reaction mixture was concentrated in vacuo, dissolved indichloromethane (25 mL) and cooled to 0° C.2-Bromo-5-methyl-pyridin-4-amine (1.10 g, 5.88 mmol) was added followedby triethylamine (3.2 mL, 23 mmol). The resulting mixture was stirredand warmed to ambient temperature over 16 hours. The reaction mixturewas diluted with water (10 mL) and extracted with dichloromethane (2×10mL). The combined organics were dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-60% ethyl acetate/petroleum ether) to provideN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(618 mg, 24%). ESI-MS m/z calc. 582.00, found 585.0 (M+1)+; retentiontime (Method F): 1.15 minutes (1.5 minute run).

Step 2: Methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

To a solution ofN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(618 mg, 1.06 mmol) in methanol (11 mL) and triethylamine (337 μL, 2.42mmol) was added Pd(dppf)Cl₂.DCM (180 mg, 0.2204 mmol). Carbon monoxidewas bubbled through the vigorously stirring reaction mixture for 5minutes. The reaction mixture was then heated at 75° C. under carbonmonoxide atmosphere for 16 hours. The reaction mixture was cooled,filtered through a pad of Celite eluting with methanol and the filtratewas concentrated in vacuo. Silica gel chromatography (30-80% ethylacetate/petroleum ether) provided methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(346 mg, 58%) as a pale yellow oil. ESI-MS m/z calc. 562.10, found 563.0(M+1)+; retention time (Method F): 1.05 minutes (1.5 minute run).

Step 3:4-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(153)

A mixture of methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(28.5 mg, 0.051 mmol) and ammonia (1.4 mL of 4 M in methanol, 5.6 mmol)was stirred at room temperature for 72 hours. The reaction mixture wasconcentrated in vacuo and purified by HPLC (37-100% acetonitrile/0.1%ammonium hydroxide) to provide4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(5 mg, 18%) as a white solid. ESI-MS m/z calc. 547.10, found 548.0(M+1)+; retention time (Method E): 3.45 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.48 (s, 2H), 8.06 (d, J=2.8 Hz,1H), 7.79-7.55 (m, 2H), 7.45-7.22 (m, 2H), 7.05 (ddd, J=8.9, 2.8, 1.3Hz, 1H), 6.84 (s, 1H), 3.81 (s, 3H), 2.31 (s, 3H) ppm.

Example 545-[[2,4-Dichloro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(183)

Step 1: 2,4-Dichloro-6-fluoro-benzoic Acid

To a solution of 2,4-dichloro-6-fluoro-benzaldehyde (1.0 g, 5.2 mmol),2-methyl-2-butene (1.8 g, 2.7 mL, 26 mmol) and sodium dihydrogenphosphate hydrate (2.14 g, 15.5 mmol) in tert-BuOH (5.0 mL)/acetonitrile(3.25 mL)/water (5.0 mL) at 0° C. was added sodium chlorite (1.41 g,15.5 mmol). The reaction mixture was at this temperature for 1 hour,then acidified with 1 M HCl (50 mL) and extracted with ethyl acetate(3×). The combined organics were washed with 1 M HCl and brine, driedover Na₂SO₄, filtered and concentrated in vacuo. Then solid wastriturated with 20% diethyl ether/hexane, filtered and washing withadditional 20% diethyl ether/hexane to provide2,4-dichloro-6-fluoro-benzoic acid (700 mg, 65%) as a white solid. ¹HNMR (400 MHz, DMSO-d6) δ 14.29 (br s, 1H), 7.70-7.63 (m, 2H) ppm.

Step 2: 2,4-Dichloro-6-fluoro-benzoyl chloride

To a solution of 2,4-dichloro-6-fluoro-benzoic acid (5.1 g, 24.4 mmol)and DMF (173 μL, 2.23 mmol) in dichloromethane (51 mL) at 0° C. wasadded oxalyl chloride (10.2 mL, 117 mmol) dropwise. The mixture wasstirred at room temperature for 5 hours under N₂ atmosphere. Conversionwas monitored by UPLC via test for morpholine adduct formation. Thesolvent was evaporated in vacuo to provide 2,4-dichloro-6-fluoro-benzoylchloride.

Step 3: 5-[(2,4-Dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide

To a solution of 2,4-dichloro-6-fluoro-benzoyl chloride (2.5 g, 11.0mmol) and DIEA (4.8 mL, 27 mmol) in 1-methyl-pyrrolidin-2-one (25 mL) at0° C. was added a solution of 5-aminopyridine-2-carboxamide (1.51 g,11.0 mmol) in dichloromethane (12.5 mL) dropwise. The reaction wasallowed to warm to room temperature and stirred for 16 hours. Thereaction mixture was diluted with water (20 mL) and the resultingsuspension was filtered to provide5-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (1.2 g,33%). ESI-MS m/z calc. 326.99, found 328.1 (M+1)+; retention time(Method B): 1.16 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.34 (s, 1H), 8.88-8.82 (m, 1H), 8.29 (dd, J=8.5, 2.5 Hz, 1H),8.12-8.01 (m, 2H), 7.76 (dq, J=4.2, 2.0 Hz, 2H), 7.58 (s, 1H) ppm.

Step 4:5-[[2,4-Dichloro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(183)

To a solution of5-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (44 mg,0.13 mmol) in DMF (1 mL) was added2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (28 mg, 0.13 mmol)followed by K₂CO₃ (56 mg, 0.40 mmol). The reaction was heated at 80° C.for 1 hour. The reaction was diluted with DMSO (0.5 mL), filtered andpurified by HPLC (1-99% acetonitrile/5 mM HCl) to provide5-[[2,4-dichloro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(41 mg, 58%). ESI-MS m/z calc. 518.05, found 518.9 (M+1)+; retentiontime (Method B): 1.83 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.23 (s, 1H), 8.86 (dd, J=2.5, 0.7 Hz, 1H), 8.27 (dd, J=8.6, 2.5 Hz,1H), 8.13-7.99 (m, 2H), 7.61-7.48 (m, 2H), 7.27 (d, J=8.8 Hz, 1H), 7.19(d, J=2.8 Hz, 1H), 7.00 (m, 1H) 6.76 (d, J=1.8 Hz, 1H) ppm.

Example 554-[[2,4-Dichloro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(179)

This compound was made in an analogous fashion to Example 54 from4-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide and2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol. The yield of thedesired product after HPLC purification was 10 mg (13%). ESI-MS m/zcalc. 518.04, found 518.9 (M+1)+; retention time (Method B): 1.6 minutes(3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.54 (d,J=5.5 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 7.82 (dd,J=5.5, 2.2 Hz, 1H), 7.66 (d, J=2.9 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.28(d, J=8.8 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.01 (ddd, J=8.8, 2.7, 1.2Hz, 1H), 6.76 (d, J=1.8 Hz, 1H) ppm.

Example 56N-(3-Carbamoyl-4-fluoro-phenyl)-3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(62)

Step 1: Ethyl 3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate

A solution of 3,5-difluoro-2-(trifluoromethyl)pyridine (9.0 g, 49 mmol)in THF (100 mL) was cooled to −78° C. and treated with LDA (27 mL of 2 Min ethylbenzene/THF/heptane, 54.00 mmol) while maintaining the internalreaction temperature below −65° C. The reaction mixture was stirred at−78° C. for 40 minutes followed by the dropwise addition ofchloroethylformate (6.1 mL, 63.8 mmol) over 10 minutes while maintaininginternal reaction temperature below −65° C. The mixture was stirred at−78° C. for 30 minutes then allowed to warm to room temperature over 1hour. The mixture was quenched by addition of saturated aqueous NH₄C₁and diluted with ethyl acetate (100 mL). The organic layer was separatedand washed with water and brine, dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-5% ethylacetate/petroleum ether) provided ethyl3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate (7.4 g, 59%) as apale yellow oil. ¹H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 4.46 (q,J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H) ppm.

Step 2: Ethyl3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate

A flask charged with ethyl3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate (1.87 g, 7.33mmol) and 4-(trifluoromethoxy)phenol (950 μL, 7.33 mmol) in DMA (20 mL)was cooled to 0° C. and treated with Cs₂CO₃ (4.78 g, 14.7 mmol) in oneportion. The reaction mixture was allowed to warm to room temperatureand stirred for 1 hour. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-10% ethyl acetate/hexanes) provided ethyl3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate(2.22 g, 73%) ESI-MS m/z calc. 413.05, found 414.2 (M+1)+; retentiontime (Method B): 2.16 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 8.50 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.38-7.31 (m, 2H), 4.31 (q,J=7.1 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H) ppm.

Step 3:3-Fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicAcid

To a solution of ethyl3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate(2.22 g, 5.37 mmol) in THF (22 mL) was added aqueous NaOH (20 mL of 3 M,60 mmol) followed by solid NaOH (500 mg, 12.5 mmol). The reactionmixture was stirred for 4 hours at room temperature then cooled to 0° C.and slowly acidified with 6 M HCl. The resulting precipitate wasfiltered and washed with water. The aqueous filtrated was extracted withdichloromethane and combined with the precipitate. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo to obtain3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (1.97 g, 95%) ESI-MS m/z calc. 385.02, found 386.0 (M+1)+;retention time (method B): 1.73 minutes (3 minute run).

Step 4:3-Fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonylchloride

To a solution of3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (200 mg, 0.519 mmol) and DMF (10 μL, 0.13 mmol) in dichloromethane(2 mL) at 0° C. was added oxalyl chloride (70 μL, 0.80 mmol) dropwise.The reaction mixture was stirred at room temperature for 30 minutes.Conversion was monitored by UPLC via test for morpholine adductformation. The solvent was evaporated under reduced pressure to afford3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonylchloride.

Step 5:N-(3-Carbamoyl-4-fluoro-phenyl)-3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(62)

A solution of 5-amino-2-fluoro-benzamide (78 mg, 0.51 mmol) and DIEA(250 μL, 1.44 mmol) in THF (3 mL) at 0° C. was treated with a solutionof3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonylchloride (200 mg, 0.496 mmol) in THF (3 mL)/dichloromethane (2 mL) underN₂ atmosphere. The reaction mixture was allowed to warm to roomtemperature and stirred for 1 hour. The mixture was diluted with waterand extracted with dichloromethane. The organic layer was washed with 1M HCl (2×), dried over MgSO₄, filtered and concentrated in vacuo. Silicagel chromatography (0-80% ethyl acetate/hexanes) providedN-(3-carbamoyl-4-fluoro-phenyl)-3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(68 mg, 26%). ESI-MS m/z calc. 521.06, found 522.1 (M+1)+; retentiontime (Method B): 1.74 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.18 (s, 1H), 8.43 (s, 1H), 7.90 (dd, J=6.4, 2.8 Hz, 1H), 7.78-7.67(m, 3H), 7.50-7.43 (m, 2H), 7.41-7.35 (m, 2H), 7.30 (dd, J=10.1, 8.9 Hz,1H) ppm.

Example 57N-(2-Carbamoyl-4-pyridyl)-3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(61)

This compound was made in an analogous fashion to Example 56, exceptemploying 4-aminopyridine-2-carboxamide in the amide formation step(Step 5). The yield of the desired product after purification was 76 mg(30%). ESI-MS m/z calc. 504.07, found 505.1 (M+1)+; retention time(Method B): 1.74 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.59 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.46 (s, 1H), 8.24 (d, J=2.1 Hz,1H), 8.12 (d, J=2.8 Hz, 1H), 7.74 (dd, J=5.5, 2.2 Hz, 1H), 7.69 (d,J=2.7 Hz, 1H), 7.49-7.42 (m, 2H), 7.42-7.34 (m, 2H) ppm.

Example 585-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(173)

Step 1: Methyl 2,6-difluoro-4-(trifluoromethoxy)benzoate

Sulfuric acid (300 μL, 5.63 mmol) was added to a solution of2,6-difluoro-4-(trifluoromethoxy)benzoic acid (677 mg, 2.80 mmol) inmethanol (6.5 mL) and the reaction was stirred at 65° C. for 14 hours.Additional sulfuric acid (300 μL, 5.628 mmol) was added to the reactionand stirred at 65° C. for an additional 17 hours. The reaction wascooled to room temperature and partitioned between water anddichloromethane. The organic layer was washed with saturated aqueousNaHCO₃ and brine dried over Na₂SO₄, filtered and carefully concentratedin vacuo at low temperature (caution: product is volatile) to providemethyl 2,6-difluoro-4-(trifluoromethoxy)benzoate (580 mg, 81%) as acolorless liquid. ¹H NMR (400 MHz, DMSO-d6) δ 7.56-7.45 (m, 2H), 3.91(s, 3H) ppm.

Step 2: Methyl2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoate

Methyl 2,6-difluoro-4-(trifluoromethoxy)benzoate (550 mg, 2.15 mmol),2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (461 mg, 2.18 mmol)and Cs₂CO₃ (2.38 g, 7.29 mmol) in DMF (7 mL) were stirred at 75° C. for20 minutes. The reaction was diluted with ethyl acetate and washed withwater and brine, dried over Na₂SO₄, filtered and concentrated in vacuo.Silica gel chromatography (0-30% ethyl acetate/hexanes) provided methyl2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoate(700 mg, 73%) as a colourless viscous liquid. ESI-MS m/z calc. 447.06,found 448.0 (M+1)+; retention time (Method C): 3.06 minutes (5 minuterun).

Step 3:2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoicAcid

A solution of methyl2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoate(660 mg, 1.48 mmol) in methanol (6 mL) was treated with aqueous NaOH (6mL of 1 M, 6 mmol). The reaction was stirred at room temperature for 2hours. Additional aqueous NaOH was added (4.5 mL of 1 M, 4.5 mmol) andthe reaction was heated at 60° C. for 4.5 hours. The reaction wasacidified to pH˜1 with 12 M HCl, then diluted with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo to provide2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoicacid (592 mg, 92%) as a viscous yellow liquid. ESI-MS m/z calc. 433.05,found 434.1 (M+1)+; retention time (Method A): 0.71 minutes (1 minuterun).

Step 4:2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoylchloride

To a solution of2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoicacid (200 mg, 0.462 mmol) and DMF (20 μL, 0.26 mmol) in dichloromethane(2 mL) at 0° C. was added oxalyl chloride (300 μL, 3.44 mmol) dropwiseunder N₂ atmosphere. The ice bath was removed after 10 minutes and thereaction allowed to warm to room temperature over 20 minutes. Conversionwas monitored by UPLC via test for piperidine adduct formation. Thesolvent was evaporated under reduced pressure to afford2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoylchloride.

Step 5:5-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(173)

To a stirring slurry of 5-aminopyridine-2-carboxamide (47 mg, 0.35 mmol)in dichloromethane (1 mL) and DIEA (80 μL, 0.46 mmol) at 0° C. was addeda slurry of cold2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoylchloride (104 mg, 0.230 mmol) in dichloromethane (1 mL) dropwise. Thereaction mixture was removed from ice bath after 10 minutes and stirredat room temperature for 18 hours. The reaction was concentrated in vacuoand purified by HPLC (10-99% acetonitrile/5 mM HCl) to provide5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(24 mg, 19%). ESI-MS m/z calc. 552.10, found 552.9 (M+1)+; retentiontime (Method C): 2.57 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.26 (s,1H), 8.84 (s, 1H), 8.26 (dd, J=8.7, 2.5 Hz, 1H), 8.07-7.95 (m, 2H), 7.55(s, 1H), 7.43-7.25 (m, 2H), 7.21 (d, J=2.8 Hz, 1H), 7.08-6.93 (m, 1H),6.56 (s, 1H) ppm.

Example 594-[[2-Fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(172)

A vial was charged with2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoicacid (prepared as described in Example 58, 100 mg, 0.231 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Preparation 1, 81 mg, 0.25 mmol), andtris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (8.5 mg, 0.024 mmol) in2-propanol (1.5 mL), and was heated at 80° C. under an atmosphere of airfor 15 hours. The reaction mixture was cooled to room temperature,diluted with ethyl acetate and 1 M HCl. The two layers were separatedand the aqueous layer was extracted with again with ethyl acetate. Thecombined organic layers was dried over Na₂SO₄, filtered and concentratedin vacuo. HPLC purification (1-99% acetonitrile/5 mM HCl) provided4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(40 mg, 31%) as a white solid. ESI-MS m/z calc. 552.10, found 553.0(M+1)+; retention time (Method C): 2.56 minutes (5 minutes run). ¹H NMR(400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.30 (d,J=2.2 Hz, 1H), 8.09 (d, J=2.6 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H),7.65 (d, J=2.8 Hz, 1H), 7.48-7.27 (m, 2H), 7.21 (d, J=2.8 Hz, 1H),7.08-6.93 (m, 1H), 6.56 (s, 1H) ppm.

Example 604-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(130)

Step 1:4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde

2-Methoxy-4-(trifluoromethoxy)phenol (2.3 g, 11.1 mmol), Cs₂CO₃ (4.8 g,14.7 mmol) and 4-chloro-2,6-difluoro-benzaldehyde (2.0 g, 11.3 mmol)were combined in DMF (12 mL) and stirred for 16 hours. The mixture wasconcentrated in vacuo and the residue was partitioned between water anddichloromethane. The organic layer was concentrated and purified bysilica gel chromatography (0-50% ethyl acetate/petroleum ether) toprovide4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde(3.4 g, 84%) as a colorless oil. ESI-MS m/z calc. 364.01, found 365.1(M+1)+; retention time (Method F): 1.08 minutes (1.5 minute run).

Step 2:4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic Acid

A suspension of4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde(3.40 g, 9.32 mmol) and sodium dihydrogen phosphate hydrate (1.3 g, 10.8mmol) in tert-butyl alcohol (20 mL)/water (10 mL) was cooled to 0° C.and treated with a solution of 2-methyl-2-butene (14 mL of 2 M in THF,28 mmol) followed by the portionwise addition of sodium chlorite (1.3 g,11.50 mmol) over 30 minutes. The mixture was allowed to warm to roomtemperature and stirred for 16 hours. The reaction mixture was acidifiedto pH1-2 using 2 M HCl and partitioned with dichloromethane. The organiclayer was dried (phase separation cartridge) and concentrated in vacuoto afford4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(3.82 g, 108%) as a white solid. ESI-MS m/z calc. 380.01, found 379.1(M−1)−; retention time (Method F): 0.71 minutes (1.5 minutes).

Step 3:4-Chloro-2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)benzoylchloride

To an ice-cooled solution of4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(1.5 g, 3.7 mmol) in dichloromethane (20 mL) was added DMF (33 μL, 0.43mmol) and oxalyl chloride (1.1 mL, 12.6 mmol). The reaction was warmedto room temperature and stirred for 3.5 hours. The reaction mixture wasconcentrated in vacuo to provide4-chloro-2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)benzoylchloride.

Step 4:N-(2-Bromo-5-methyl-4-pyridyl)-4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide

To a solution of4-chloro-2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)benzoylchloride (3.7 mmol) in dichloromethane (20 mL) at 0° C. were added2-bromo-5-methyl-pyridin-4-amine (900 mg, 4.81 mmol) and triethylamine(2.7 mL, 19 mmol). The reaction mixture was allowed to warm to roomtemperature and stirred for 16 hours. The mixture was diluted with waterand extracted with dichloromethane. The combined organics were driedover MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-20% ethyl acetate/petroleum ether) providedN-(2-bromo-5-methyl-4-pyridyl)-4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(742 mg, 36%) as a white solid. ESI-MS m/z calc. 547.98, found 551.0(M+1)+; retention time (Method F): 1.13 minutes (1.5 minute run).

Step 5: Methyl4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

To a solution ofN-(2-bromo-5-methyl-4-pyridyl)-4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(742 mg, 1.35 mmol) in methanol (13 mL) and triethylamine (430 μL, 3.09mmol) was added Pd(dppf)Cl₂.DCM (229 mg, 0.280 mmol). Carbon monoxidewas bubbled through the vigorously stirring mixture for 5 minutes. Thereaction mixture was heated at 75° C. under carbon monoxide atmospherefor 16 hours. The reaction mixture was filtered through a pad of Celite.The Celite was rinsed with methanol and the filtrate concentrated invacuo. Silica gel chromatography (30-80% ethyl acetate/petroleum ether)provided methyl4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(593 mg, 83%) as a pale yellow clear oil. ESI-MS m/z calc. 528.07, found529.0 (M+1)+; retention time (Method F): 1.03 minutes (1.5 minute run).

Step 6:4-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(130)

A mixture of methyl4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(35 mg, 0.07 mmol) and ammonia (1.83 mL of 7 M in methanol, 12.81 mmol)was stirred at room temperature for 16 hours. SPM32 silica metalscavenger (150 mg) was added and the reaction was stirred for 15minutes. The mixture was filtered and the filtrate concentrated invacuo. Silica gel chromatography (0-100% ethyl acetate/petroleum ether)provided4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(6.8 mg, 20%) as a white solid. ESI-MS m/z calc. 513.07, found 514.0(M+1)+; retention time (Method E): 3.37 minutes (5 minute run). ¹H NMR(500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.46 (s, 2H), 8.04 (d, J=2.8 Hz,1H), 7.59 (s, 1H), 7.35 (dd, J=29.9, 8.8 Hz, 2H), 7.23 (d, J=2.7 Hz,1H), 7.12-6.95 (m, 1H), 6.61 (s, 1H), 3.82 (s, 3H), 2.29 (s, 3H) ppm.

Example 615-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(185)

This compound was made in an analogous fashion toN-(2-bromo-5-methyl-4-pyridyl)-4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(Example 60, step 4) except employing 5-aminopyridine-2-carboxamide inthe amide formation step. The yield of the desired product afterpurification was 65 mg (45%). ESI-MS m/z calc. 499.06, found 499.9(M+1)+; 497.9 (M−1)−; retention time (Method E): 3.15 minutes (5 minuterun). ¹H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.83 (d, J=2.4 Hz, 1H),8.24 (dd, J=8.6, 2.5 Hz, 1H), 8.06-7.97 (m, 2H), 7.54 (s, 1H), 7.39 (dd,J=8.8, 1.8 Hz, 1H), 7.28 (d, J=8.9 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H),7.03-6.95 (m, 1H), 6.64 (t, J=1.5 Hz, 1H), 3.77 (s, 3H) ppm.

Example 624-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(170)

Step 1: Methyl4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

This compound was made in an analogous fashion toN-(2-bromo-5-methyl-4-pyridyl)-4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(Example 60, step 4) except employing methyl4-aminopyridine-2-carboxylate in the amide formation step. The yield ofthe desired product after purification was 280 mg (69%). ESI-MS m/zcalc. 514.06, found 515.2 (M+1)+; retention time (Method F): 1.01minutes (1.5 minute run).

Step 2:4-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(170)

Methyl4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(270 mg, 0.525 mmol) was stirred in ammonia (8.4 mL of 7 M in methanol,58.8 mmol) for 16 hours under N₂ atmosphere. The reaction mixture wasconcentrated in vacuo. The residue was triturated with ethyl acetate andether to provide4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(212 mg, 78%). ESI-MS m/z calc. 499.06, found 500.0 (M+1)+; retentiontime (Method E): 3.32 minutes (5 minute run). ¹H NMR (500 MHz, DMSO-d6)δ 11.30 (s, 1H), 8.64-8.48 (m, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.09 (d,J=2.8 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d, J=2.8 Hz, 1H),7.49-7.15 (m, 3H), 7.01 (ddd, J=8.7, 2.7, 1.2 Hz, 1H), 6.64 (t, J=1.5Hz, 1H), 3.79 (s, 3H) ppm.

Example 634-[[3-(Difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(155)

Step 1: 6-Bromo-2-fluoro-3-hydroxy-benzaldehyde

A solution of 6-bromo-2-fluoro-3-methoxy-benzaldehyde (2.0 g, 8.6 mmol)in dichloromethane (45 mL) under a N₂ balloon was cooled to −78° C.Boron tribromide (10 mL of 1 M, 10 mmol) was added dropwise under N₂atmosphere. The reaction was stirred at room temperature for 16 hours.The mixture was cooled to 0° C. and the excess boron tribromide wasquenched with saturated NaHCO₃ solution. Water was added and thesolution was extracted with dichloromethane (3×). The combined organiclayers were washed with brine, dried over Na₂SO₄, and filtered andconcentrated in vacuo to provide 6-bromo-2-fluoro-3-hydroxy-benzaldehyde(1.26 g, 67%). ESI-MS m/z calc. 217.94, found 220.9 (M+2)+; retentiontime (Method A): 0.41 minutes (1 minute run).

Step 2: 6-Bromo-3-(difluoromethoxy)-2-fluoro-benzaldehyde

A flask charged with 6-bromo-2-fluoro-3-hydroxy-benzaldehyde (610 mg,2.79 mmol), sodium chlorodifluoroacetate (910 mg, 5.97 mmol), K₂CO₃ (385mg, 2.79 mmol), DMF (10 mL) and water (1 mL) was heated under N₂atmosphere at 100° C. for 2 hours. The reaction mixture was cooled toroom temperature and partitioned between water and ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-20% ethylacetate/hexanes) provided6-bromo-3-(difluoromethoxy)-2-fluoro-benzaldehyde (280 mg, 37%). ESI-MSm/z calc. 267.93, found 270.9 (M+1)+; retention time (Method A): 0.57minutes (1 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 10.17 (d, J=0.9 Hz,1H), 7.70 (dd, J=8.9, 1.7 Hz, 1H), 7.62 (ddt, J=8.9, 8.0, 0.8 Hz, 1H),7.31 (t, J=72.6 Hz, 1H) ppm.

Step 3: 6-Bromo-3-(difluoromethoxy)-2-fluoro-benzoic Acid

To a solution of 6-bromo-3-(difluoromethoxy)-2-fluoro-benzaldehyde (580mg, 2.16 mmol) in tert-BuOH (6 mL), water (3 mL) and acetonitrile (3 mL)was added sodium dihydrogen phosphate hydrate (395 mg, 3.29 mmol)followed by 2-methyl-2-butene (1.7 mL, 16 mmol) and the portionwiseaddition of sodium chlorite (300 mg, 3.312 mmol). The reaction mixturewas stirred at room temperature for 45 minutes. The reaction wasadjusted to pH-2 with 1 M HCl solution. The layers were separated andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were dried over MgSO₄, filtered and concentrated in vacuo toprovide 6-bromo-3-(difluoromethoxy)-2-fluoro-benzoic acid (575 mg, 94%)as a white solid. ESI-MS m/z calc. 283.93, found 287.0 (M+1)+; retentiontime (Method A): 0.43 minutes (1 minute run).

Step 4:3-(Difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicAcid

To a pressure flask was added6-bromo-3-(difluoromethoxy)-2-fluoro-benzoic acid (570 mg, 2.00 mmol),2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (423 mg, 2.00 mmol)and Cs₂CO₃ (820 mg, 2.51 mmol), and toluene (7 mL). The reaction mixturewas bubbled with N₂ for 10 min, then copper (I) iodide (170 mg, 0.893mmol) was added. The flask was flushed with N₂, sealed and heated at100° C. with vigorous stirring for 4 hours. The mixture was allowed tocool then diluted with ethyl acetate and water. The water layer wasacidified with HCl and the product extracted into the ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated. Silica gel chromatography (0-100% ethyl acetate/hexanes)provided3-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (280 mg, 34%). ESI-MS m/z calc. 415.06, found 416.1 (M+1)+;retention time (Method B): 1.69 minutes (3 minute run).

Step 5:4-[[3-(Difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(155)

A vial was charged with3-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (75 mg, 0.18 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Preparation 1, 62 mg, 0.19 mmol),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (3.1 mg, 0.0088 mmol) in2-propanol (1.25 mL) and heated at 83° C. under an air atmosphere for 24hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was partitioned betweendichloromethane and 1N HC. The organic layer was dried over MgSO₄,filtered and concentrated. Silica gel chromatography (0-60% ethylacetate/hexanes) provided4-[[3-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(20 mg, 21%). ESI-MS m/z calc. 534.10, found 535.2 (M+1)+; retentiontime (Method B): 1.63 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.35 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.09(s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (s, 1H), 7.50-7.22 (i, 3H),7.19 (d, J=2.8 Hz, 1H), 7.07-6.92 (i, 1H), 6.62 (dd, J=9.1, 1.6 Hz, 1H)ppm.

Example 645-[[3-(Difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(198)

To a solution of3-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (100 mg, 0.241 mmol) in dichloromethane (3 mL) and DMF (19 μL, 0.24mmol) at 0° C. was added oxalyl chloride (21 μL, 0.24 mmol) dropwiseunder N₂ atmosphere. The reaction mixture was allowed to warm to roomtemperature then stirred for 30 minutes. The solution was then addeddropwise to a stirring solution of 5-aminopyridine-2-carboxamide (50 mg,0.36 mmol) in dichloromethane (3 mL) and DIEA (210 μL, 1.20 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature andstirred for 16 hours. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was washed with 1 M HCl,dried over MgSO₄, filtered and concentrated in vacuo. HPLC purification(1-99% acetonitrile/5 mM HCl) provided5-[[3-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(36 mg, 27%). ESI-MS m/z calc. 534.11, found 535.3 (M+1)+; retentiontime (Method B): 1.63 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.27 (s, 1H), 8.91-8.74 (m, 1H), 8.27 (dd, J=8.6, 2.5 Hz, 1H),8.10-7.96 (m, 2H), 7.56 (s, 1H), 7.49-7.01 (m, 4H), 6.99 (ddt, J=8.8,2.4, 1.2 Hz, 1H), 6.63 (dd, J=9.2, 1.6 Hz, 1H) ppm.

Example 65 Racemictrans-N-(3-Carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxamide(106)

Step 1: Methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

To a solution of methyl 6-bromo-4-chloro-pyridine-3-carboxylate (8.48 g,33.9 mmol) was dissolved in anhydrous DMF (85 mL) under N₂ atmosphere at0° C. was added 2-methoxy-4-(trifluoromethoxy)phenol (7.05 g, 33.9 mmol)in one portion followed by Cs₂CO₃ (33.1 g, 102 mmol). The reaction wasstirred for 10 minutes then allowed to warm to room temperature andstirred for 2 hours. The mixture was partitioned between ethyl acetateand brine and the layers were separated. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo.Silica gel chromatography (0-10% ethyl acetate/hexanes) provided methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(11.5 g, 80%) as a white solid. ESI-MS m/z calc. 420.98, found 422.06(M+1)+; retention time (Method A): 0.75 minutes (1 minute run). ¹H NMR(500 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.27 (d,J=2.2 Hz, 1H), 7.04 (d, J=10.0 Hz, 1H), 6.78 (s, 1H), 3.84 (s, 3H), 3.78(s, 3H) ppm.

Step 2: Methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[(E)-prop-1-enyl]pyridine-3-carboxylate

Methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(2.0 g, 4.74 mmol), trans-1-propenylboronic acid pinacol ester (955 mg,5.68 mmol), and Pd(dppf)Cl₂.DCM (170 mg, 0.232 mmol) were brought up inacetonitrile (20 mL), aqueous K₂CO₃ solution (12 mL of 2 M, 24 mmol) andDMF (7 mL). The reaction stirred at 60° C. for 1 hour, then the heat wasreduced to 40° C. and stirring continued for 16 hours. The reaction wascooled, diluted with ether and washed with 50% saturated aqueous NaHCO₃solution and brine. The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo. Silica gel chromatography (80 g silica, 0-40%ethyl acetate/hexanes) provided methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[(E)-prop-1-enyl]pyridine-3-carboxylate(1.325 g, 73%). ESI-MS m/z calc. 383.10, found 384.2 (M+1)+; retentiontime (Method A): 0.6 minutes (1 minute run). ¹H NMR (400 MHz, DMSO-d6) δ8.82 (s, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.04 (ddd,J=8.8, 2.7, 1.2 Hz, 1H), 6.89-6.77 (m, 1H), 6.49 (s, 1H), 6.46 (dd,J=15.4, 1.7 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 1.84 (dd, J=6.9, 1.7Hz, 3H) ppm.

Step 3: Racemic Methyltrans-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxylate

To a stirring suspension of trimethylsulfoxonium iodide (1.15 g, 5.23mmol) in DMSO (10 mL) and THF (10 mL) was added potassium tert-butoxide(600 mg, 5.35 mmol) in one portion under N₂ atmosphere. After 30 minutesa solution of methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[(E)-prop-1-enyl]pyridine-3-carboxylate(1000 mg, 2.609 mmol) in THF (10 mL) was added. The mixture was stirredat room temperature for 3 hours. The reaction was diluted with water andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-50% ethyl acetate/hexanes) provided racemic methyltrans-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxylate(750 mg, 72%). ESI-MS m/z calc. 397.11, found 398.3 (M+1)+; retentiontime (Method A): 0.61 minutes (1 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 8.72 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.04(ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.52 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H),1.80 (dt, J=8.4, 4.4 Hz, 1H), 1.40-1.27 (m, 1H), 1.15-1.09 (m, 1H), 1.08(d, J=6.0 Hz, 3H), 0.76 (ddd, J=8.2, 6.0, 3.5 Hz, 1H) ppm.

Step 4: Racemictrans-4-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxylicAcid

A solution of racemic methyltrans-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxylate(750 mg, 1.89 mmol) in methanol (5 mL) at 0° C. was treated with coldaqueous NaOH (3.8 mL of 1 M, 3.8 mmol). The reaction mixture was allowedto come to room temperature and stirred for 2 hours, then concentrated.The crude reaction was partitioned between 1 N HCl and dichloromethane.The dichloromethane was dried over Na₂SO₄, filtered and concentrated toprovide racemictrans-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxylicacid (720 mg, 99%). ESI-MS m/z calc. 383.10, found 384.3 (M+1)+;retention time (Method A): 0.51 minutes (1 minute). ¹H NMR (400 MHz,DMSO-d6) δ 8.76 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H),7.07 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.68 (s, 1H), 3.81 (s, 3H), 2.00(dt, J=8.8, 4.6 Hz, 1H), 1.54-1.40 (m, 1H), 1.28 (dt, J=8.8, 4.5 Hz,1H), 1.12 (d, J=6.0 Hz, 3H), 1.03-0.91 (m, 1H) ppm.

Step 5: Racemictrans-N-(3-Carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxamide(106)

Racemictrans-4-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxylicacid (103 mg, 0.269 mmol) and HATU (103 mg, 0.271 mmol) were combined inDMF (1 mL) and DIEA (94 μL, 0.54 mmol) and stirred for 5 minutes.5-Amino-2-fluoro-benzamide (62 mg, 0.40 mmol) was added in one portionand the reaction stirred at 45° C. for 1 hour. The reaction was dilutedwith ethyl acetate and washed with 50% saturated aqueous NaHCO₃ andbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Silicagel chromatography (0-15% methanol/dichloromethane) provided racemictrans-N-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxamide(135 mg, 95%). ESI-MS m/z calc. 519.14, found 520.2 (M+1)+; retentiontime (Method B): 1.36 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.38 (s, 1H), 8.54 (s, 1H), 7.99 (dd, J=6.4, 2.8 Hz, 1H), 7.82 (ddd,J=8.9, 4.4, 2.8 Hz, 1H), 7.70 (s, 1H), 7.67 (s, 1H), 7.45 (d, J=8.8 Hz,1H), 7.32-7.21 (m, 2H), 7.07 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.55 (s,1H), 3.80 (s, 3H), 1.81 (dt, J=8.5, 4.4 Hz, 1H), 1.38-1.25 (m, 1H),1.16-1.11 (m, 1H), 1.10 (d, J=6.0 Hz, 3H), 0.74 (ddd, J=9.0, 5.9, 3.6Hz, 1H) ppm. SFC purification (36% methanol/64% CO₂, ChiralPak IG(250×21.2 mm) 5 μm column, flow=70 mL/min) provided separatedenantiomersrel-N-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-((1S,2S)-2-methylcyclopropyl)pyridine-3-carboxamide(113) andrel-N-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-((1R,2R)-2-methylcyclopropyl)pyridine-3-carboxamide(114). The absolute stereochemistry of enantiomers 113 and 114 was notdetermined.

Example 66 Racemictrans-4-(4-(2-Methoxy-4-(trifluoromethoxy)phenoxy)-6-(2-methylcyclopropyl)nicotinamido)picolinamide(109)

Step 1: Racemictrans-4-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carbonylchloride

To a suspension of racemictrans-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxylicacid (460 mg, 1.20 mmol) and DMF (9 μL, 0.1162 mmol) in dichloromethane(7 mL) at 0° C. was added oxalyl chloride (315 μL, 3.61 mmol) dropwise.The reaction was allowed to come to room temperature and stirred for 30minutes. Conversion to the desired acid chloride was monitored by UPLCvia test for morpholine adduct formation. The reaction mixture wasconcentrated in vacuo then evaporated with dichloromethane (3×55 mL) toprovide racemictrans-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carbonylchloride.

Step 2: Racemictrans-N-(2-Carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxamide(109)

4-Aminopyridine-2-carboxamide (102 mg, 0.744 mmol) was dissolved indichloromethane (2.5 mL) and DIEA (260 μL, 1.49 mmol) and cooled to −10°C. A solution of cold (−10° C.) racemictrans-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carbonylchloride (240 mg, 0.597 mmol) in dichloromethane (2.5 mL) was addeddropwise to the stirring amine solution. The resulting suspension wasslowly allowed to warm to room temperature over 1 hour. DMF (0.5 mL) wasadded and the reaction was stirred for 1 additional hour. The reactionwas diluted with ethyl acetate and washed with 50% saturated sodiumcarbonate, water, and brine. The reaction mixture was concentrated invacuo and purified by silica gel chromatography (40 g silica, 0-10%methanol/dichloromethane). Additional silica gel chromatography (40 gsilica, 0-40% ethyl acetate/dichloromethane) provided racemictrans-N-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(2-methylcyclopropyl)pyridine-3-carboxamide(85 mg, 27%). ESI-MS m/z calc. 502.15, found 503.4 (M+1)+; retentiontime (Method B): 1.41 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.82 (s, 1H), 8.56 (s, 1H), 8.52 (d, J=5.4 Hz, 1H), 8.30 (d, J=2.1Hz, 1H), 8.11 (d, J=2.8 Hz, 1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (d,J=3.0 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.7 Hz, 1H), 7.07(ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.58 (s, 1H), 3.79 (s, 3H), 1.83 (dt,J=8.4, 4.4 Hz, 1H), 1.39-1.28 (m, 1H), 1.16-1.12 (m, 1H), 1.10 (d, J=5.9Hz, 3H), 0.80-0.70 (m, 1H) ppm. SFC purification (36% methanol/64% CO₂,ChiralPak IG (250×21.2 mm) 5 μm column, flow=70 mL/min) providedseparated enantiomersrel-N-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-((1S,2S)-2-methylcyclopropyl)pyridine-3-carboxamide(111) andrel-N-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-((1R,2R)-2-methylcyclopropyl)pyridine-3-carboxamide(112). The absolute stereochemistry of enantiomers 111 and 112 was notdetermined.

Example 676-tert-Butyl-N-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(93)

Step 1: ethyl6-tert-butyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

A vial charged with ethyl 6-tert-butyl-4-chloro-pyridine-3-carboxylate(1.56 g, 6.45 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (1.5 g, 7.2mmol) and Cs₂CO₃ (6.3 g, 19 mmol) in DMF (15 mL) was heated at 80° C.for 16 hours. The reaction mixture was quenched with 1N HCl and theaqueous layer was extracted with ethyl acetate. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-30% ethyl acetate/hexanes) provided ethyl6-tert-butyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(1.92 g, 72%). ESI-MS m/z calc. 413.15, found 414.1 (M+1)+; retentiontime (Method A): 0.7 minutes (1 minute run).

Step 2:6-tert-Butyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicAcid

To a solution of ethyl6-tert-butyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(1.90 g, 4.60 mmol) in methanol (20 mL) and water (15 mL) was addedsolid NaOH (1.8 g, 45.00 mmol). The reaction mixture was stirred at roomtemperature for 2 hours then cooled to 0° C. and slowly acidified with6N HCl. The mixture was extracted with ethyl acetate, and the organiclayer was dried over MgSO₄, filtered and concentrated in vacuo to obtain6-tert-butyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (1.64 g, 93%). ESI-MS m/z calc. 385.1137, found 386.2 (M+1)+;retention time (Method B): 1.41 minutes (3 minute run).

Step 3:6-tert-Butyl-N-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(93)

A pressure flask was charged with6-tert-butyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (200 mg, 0.519 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Preparation 1, 188 mg, 0.572 mmol),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (5.3 mg, 0.015 mmol) in2-propanol (2 mL) and heated at 83° C. under an atmosphere of air for 20hours. The reaction mixture was cooled to room temperature and thesolvent was evaporated. Silica gel chromatography (0-60% ethylacetate/hexanes) provided6-tert-butyl-N-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(83 mg, 32%). ESI-MS m/z calc. 504.16, found 505.2 (M+1)+; retentiontime (Method B): 1.5 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ10.97 (s, 1H), 8.69 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.1 Hz,1H), 8.10 (d, J=2.8 Hz, 1H), 7.89 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (d,J=2.9 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.06(ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.58 (s, 1H), 3.77 (s, 3H), 1.22 (s, 9H)ppm.

Example 686-tert-Butyl-N-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(94)

To a solution of6-tert-butyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (prepared as described in Example 67, Step 2, 200 mg, 0.519 mmol),5-amino-2-fluoro-benzamide (80 mg, 0.52 mmol) and HATU (218 mg, 0.573mmol) in DMF (2 mL) was added 4-methylmorpholine (200 μL, 1.82 mmol) andthe reaction mixture was stirred for 20 hours. The reaction mixture wasdiluted with water and the aqueous layer was extracted by ethyl acetate.The organic layer was washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The crude material was purified by HPLC (1-99%acetonitrile/5 mM HCl)). The product fractions were neutralized withsaturated aqueous NaHCO₃ and extracted with dichloromethane. The organiclayer was dried over MgSO₄, filtered and concentrated to obtain6-tert-butyl-N-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(155 mg, 57%). ESI-MS m/z calc. 521.16, found 522.2 (M+1)+; retentiontime (Method B): 1.49 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.54 (s, 1H), 8.66 (s, 1H), 8.00 (dd, J=6.5, 2.8 Hz, 1H), 7.84-7.78(m, 1H), 7.69 (d, J=14.6 Hz, 2H), 7.42 (d, J=8.8 Hz, 1H), 7.30-7.22 (m,2H), 7.06 (dd, J=9.0, 2.6 Hz, 1H), 6.55 (s, 1H), 3.78 (s, 3H), 1.21 (s,9H) ppm.

Example 69N-(3-Carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxamide(102)

Step 1: Methyl6-isopropenyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

A flask charged with methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(1.96 g, 4.64 mmol), isopropenylboronic acid pinacol ester (1.04 g, 6.19mmol), Pd(dppf)Cl₂.DCM (380 mg, 0.465 mmol) and aqueous K₂CO₃ (5 mL of 2M, 10 mmol) in acetonitrile (20 mL) was flushed with argon and heated at80° C. for 2 hours. The reaction mixture was cooled to room temperatureand partitioned between water and ethyl acetate. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-30% ethyl acetate/hexanes) provided methyl6-isopropenyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(1.09 g, 61%). ESI-MS m/z calc. 383.10, found 384.2 (M+1)+; retentiontime (Method B): 1.65 minutes (3 minute run).

Step 2: Methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxylate

To a stirred suspension of trimethylsulfoxonium iodide (1.38 g, 6.26mmol) in DMSO (12 mL) and THF (12 mL) was added potassium tert-butoxide(703 mg, 6.26 mmol) in one portion under N₂ atmosphere. After 30 minutesa solution of methyl6-isopropenyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(1.20 g, 3.13 mmol)methyl in THF (1 mL) was added. The mixture wasstirred for 3 hours then partitioned between water and with ethylacetate. The organic layer was washed with water and brine, dried overMgSO₄ and concentrated in vacuo. Silica gel chromatography (0-30% ethylacetate/hexanes) provided methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxylate(486 mg, 39%). ESI-MS m/z calc. 397.11, found 398.2 (M+1)+; retentiontime (Method B): 1.72 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 8.77 (s, 1H), 7.34-7.26 (m, 2H), 7.09-7.01 (m, 1H), 6.44 (s, 1H), 3.81(s, 3H), 3.79 (s, 3H), 1.22 (s, 3H), 1.17 (q, J=3.5 Hz, 2H), 0.83 (q,J=3.6 Hz, 2H) ppm.

Step 3:4-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxylicAcid

To a flask charged with methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxylate(500 mg, 1.26 mmol) in methanol (5 mL), THF (5 mL) and water (5 mL) wasadded solid NaOH (510 mg, 12.8 mmol) and the reaction mixture wasstirred at room temperature for 45 minutes. The solvent was evaporatedand the residue was taken up in water, cooled in an ice bath andquenched slowly with 6 M HCl. The resulting suspension was extractedwith ethyl acetate, dried over MgSO₄, filtered and concentrated in vacuoto obtain4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxylicacid (469 mg, 97%). ESI-MS m/z calc. 383.10, found 384.1 (M+1)+;retention time (Method B): 1.34 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 8.77 (s, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.05 (ddq, J=8.7, 2.4,1.2 Hz, 1H), 6.44 (d, J=1.0 Hz, 1H), 3.80 (s, 3H), 1.23 (s, 3H), 1.16(q, J=3.5 Hz, 2H), 0.83 (q, J=3.6 Hz, 2H) ppm.

Step 4:N-(3-Carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxamide(102)

To a solution of4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxylicacid (127 mg, 0.331 mmol), 5-amino-2-fluoro-benzamide, (51 mg, 0.33mmol) and HATU (139 mg, 0.364 mmol) in DMF (1.3 mL) was added4-methylmorpholine (109 μL, 0.994 mmol) and the reaction mixture wasstirred for 1 hour. The reaction mixture was filtered and purified byHPLC (1-99% acetonitrile/5 mM HCl). Product fractions were neutralizedwith saturated aqueous NaHCO₃. The fractions were extracted withdichloromethane, dried over MgSO₄, filtered and concentrated to provideN-(3-carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxamide(100 mg, 58%). ESI-MS m/z calc. 519.14, found 520.1 (M+1)+; retentiontime (Method B): 1.52 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.43 (s, 1H), 8.60 (s, 1H), 7.98 (dd, J=6.5, 2.8 Hz, 1H), 7.81 (ddd,J=7.6, 4.4, 2.8 Hz, 1H), 7.69 (d, J=13.0 Hz, 2H), 7.44 (d, J=8.8 Hz,1H), 7.33-7.22 (m, 2H), 7.07 (ddd, J=8.7, 2.7, 1.3 Hz, 1H), 6.49 (s,1H), 3.79 (s, 3H), 1.27 (s, 3H), 1.15 (q, J=3.4 Hz, 2H), 0.82 (q, J=3.6Hz, 2H) ppm.

Example 70N-(2-Carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxamide(105)

A solution of4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxylicacid (102 mg, 0.266 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Preparation 1, 88 mg, 0.27 mmol),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (2.6 mg, 0.007 mmol) in2-propanol (1.5 mL) was heated at 80° C. under an atmosphere of air for20 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. Silica gel chromatography (0-60% ethylacetate/hexanes) providedN-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(1-methylcyclopropyl)pyridine-3-carboxamide(26 mg, 19%). ESI-MS m/z calc. 502.15, found 503.2 (M+1)+; retentiontime (Method B): 1.44 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.86 (s, 1H), 8.62 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.1Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 7.89 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d,J=3.0 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.8 Hz, 1H), 7.06(ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.52 (s, 1H), 3.78 (s, 3H), 1.28 (s, 3H),1.17 (q, J=3.5 Hz, 2H), 0.84 (q, J=3.6 Hz, 2H) ppm.

Example 714-[[4-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carbonyl]amino]-6-methyl-pyridine-2-carboxamide(84)

Step 1:4-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylicAcid

4-Chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid (8.00 g, 35.5mmol), finely ground K₂CO₃ (14.7 g, 106 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (7.35 g, 35.3 mmol) were combinedin DMF (65 mL) in a 150-mL pressure vessel and heated at 90° C. for 16hours. The reaction mixture was cooled to room temperature, diluted withethyl acetate, and washed with aqueous HCl (180 mL of 1 M, 180.0 mmol),water and brine. The organic phase was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The resulting solid was slurried in approximately1:30 dichloromethane/hexane. The slurry was filtered and washed with thesame dichloromethane/hexane solvent mix. The resulting solid was driedunder vacuum to provide4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylicacid (8.83 g, 63%). ESI-MS m/z calc. 397.04, found 398.0 (M+1)+;retention time (Method A): 0.68 minutes (1 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 13.80 (br s, 1H), 9.02 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.31(d, J=2.8 Hz, 1H), 7.08 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.93 (s, 1H),3.78 (s, 3H) ppm.

Step 2:4-[[4-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carbonyl]amino]-6-methyl-pyridine-2-carboxamide(84)

To a solution of4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylicacid (75 mg, 0.17 mmol) in dichloromethane (3.6 mL) at 0° C. was addedDMF (7.5 μL, 0.097 mmol) and oxalyl chloride (68 μL, 0.78 mmol). Themixture was warmed to room temperature over 30 minutes and stirred for 1hour. The reaction mixture was concentrated in vacuo. The residue wasdissolved in dichloromethane (3.6 mL) and4-amino-6-methyl-pyridine-2-carboxamide (40 mg, 0.26 mmol) was addedfollowed by triethylamine (120 μL, 0.86 mmol). The resulting mixture wasstirred at room temperature for 45 minutes then concentrated in vacuo.The residue was dissolved in DMSO and purified by HPLC (10-95%acetonitrile/0.05% TFA in water). Product fractions were combined andlyophilized to provide4-[[4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carbonyl]amino]-6-methyl-pyridine-2-carboxamidetrifluoroacetate (2 mg, 2%) as a white powder. ESI-MS m/z calc. 530.10,found 531.1 (M+1)+; 529.0 (M−1)−; retention time (Method E): 3.24minutes (5 minute run). ¹H NMR (500 MHz, Methanol-d4) δ 8.96 (d, J=0.7Hz, 1H), 8.22-8.16 (m, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.48-7.42 (m, 1H),7.23-7.16 (m, 1H), 7.09-7.01 (m, 2H), 3.84 (s, 3H), 2.64 (m, 3H) ppm.

Example 72N-(2-Carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide(34)

This compound was made in an analogous fashion to Example 71, exceptemploying 4-aminopyridine-2-carboxamide in the amide formation step(Step 2). The yield of the desired product after purification was 550 mg(34%). ESI-MS m/z calc. 516.09, found 517.2 (M+1)+; retention time(Method B): 1.67 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.29 (s, 1H), 8.96 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.34 (d, J=2.1 Hz,1H), 8.15 (s, 1H), 7.93-7.86 (m, 1H), 7.70 (s, 1H), 7.51 (d, J=8.8 Hz,1H), 7.28 (d, J=2.8 Hz, 1H), 7.10-7.03 (m, 2H), 3.78 (s, 3H) ppm.

Example 73N-(3-Carbamoyl-4-fluoro-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide(30)

This compound was made in an analogous fashion to Example 71 exceptemploying 5-amino-2-fluoro-benzamide in the amide formation step (Step2). The yield of the desired product after purification was 2.2 g (66%).ESI-MS m/z calc. 533.08, found 534.1 (M+1)+; retention time (Method B):1.78 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H),8.92 (s, 1H), 8.00 (dd, J=6.5, 2.8 Hz, 1H), 7.82 (ddd, J=8.9, 4.4, 2.8Hz, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.34-7.26(m, 2H), 7.09 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 7.02 (s, 1H), 3.79 (s, 3H)ppm.

Example 74N-(3-Carbamoylphenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide(29)

This compound was made in an analogous fashion to Example 71 exceptemploying 3-aminobenzamide in the amide formation step (Step 2). Theyield of the desired product after purification was 43 mg (58%). ESI-MSm/z calc. 515.09, found 516.1 (M+1)+; retention time (Method B): 1.66minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 8.92(s, 1H), 8.17 (t, J=1.9 Hz, 1H), 7.98 (s, 1H), 7.85 (ddd, J=8.2, 2.3,1.0 Hz, 1H), 7.62 (dt, J=7.8, 1.3 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.44(t, J=7.9 Hz, 1H), 7.39 (s, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.09 (ddd,J=8.8, 2.7, 1.3 Hz, 1H), 7.02 (s, 1H), 3.79 (s, 3H) ppm.

Example 75N-(3-Carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(74)

Step 1: Ethyl 6-bromo-3-(difluoromethyl)-2-fluoro-benzoate

4-Bromo-1-(difluoromethyl)-2-fluoro-benzene (4.90 g, 21.8 mmol) wasdissolved in anyhdrous THF (20 mL) under N₂ atmosphere and cooled to−78° C. A solution of LDA (11 mL of 2 M in THF/heptane/benzene, 22 mmol)was further diluted with anyhdrous THF (500 mL) and this solution wasadded dropwise to the reaction mixture over a period of 1 hour whilemaintaining the internal temperature below −70° C. Stirring wascontinued at −78° C. for 1 hour. Ethyl chloroformate (4.2 mL, 44 mmol)as a solution in THF (6 mL) was then added dropwise to the reactionmixture while maintaining internal temperature below −70° C. Thereaction was allowed to warm to room temperature and stirred for 16hours. The reaction was then quenched with saturated aqueous NH₄Cl andextracted with ethyl acetate (2×). The combined organics were dried overNa₂SO₄, filtered and concentrated in vacuo. Silica gel chromatography(0-3% ethyl acetate/hexanes) provided ethyl6-bromo-3-(difluoromethyl)-2-fluoro-benzoate (2.77 g, 43%). ESI-MS m/zcalc. 295.97, found 299.0 (M+1)+; retention time (Method B): 1.72minutes (3 minute run). ¹H NMR (500 MHz, DMSO-d6) δ 7.72 (h, J=8.2, 7.6Hz, 2H), 7.23 (t, J=53.9 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1Hz, 3H) ppm.

Step 2: 6-Bromo-3-(difluoromethyl)-2-fluoro-benzoic Acid

To a solution of ethyl 6-bromo-3-(difluoromethyl)-2-fluoro-benzoate (2.5g, 8.4 mmol) in methanol (25 mL) and water (25 mL) was added NaOH (3.4g, 85 mmol). The reaction mixture was stirred at room temperature for 2hours. The reaction mixture was cooled to 0° C., quenched slowly with 6NHCl and the mixture was extracted with ethyl acetate. The organic layerwas dried over MgSO₄, filtered and concentrated in vacuo to provide6-bromo-3-(difluoromethyl)-2-fluoro-benzoic acid (1.4 g, 62%). ESI-MSm/z calc. 267.95, found 271.0 (M+1)+; retention time (Method A): 0.42minutes (1 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 7.72(d, J=8.4 Hz, 1H), 7.69-7.60 (m, 1H), 7.24 (t, J=53.9 Hz, 1H) ppm.

Step 3:3-(Difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic Acid

To a pressure flask was added6-bromo-3-(difluoromethyl)-2-fluoro-benzoic acid (1.00 g, 3.72 mmol),4-(trifluoromethoxy)phenol (485 μL, 3.74 mmol) and Cs₂CO₃ (1.5 g, 4.6mmol) and toluene (12 mL). The reaction mixture was bubbled with N₂ for10 min, and then copper (I) iodide (285 mg, 1.50 mmol) was added. Theflask was flushed with N₂, capped, and heated at 100° C. with vigorousstirring for 5 hours. The mixture was allowed to cool then partitionedbetween ethyl acetate and water. The water layer was acidified with HCland the product was extracted into the ethyl acetate. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. Silica gel chromatography (0-100% ethyl acetate/hexanes) provided3-(difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid(760 mg, 56%). ESI-MS m/z calc. 366.03, found 367.0 (M+1)+; retentiontime (Method B): 1.75 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 13.99 (s, 1H), 7.71 (t, J=8.4 Hz, 1H), 7.49-7.39 (m, 2H), 7.39-7.06(m, 3H), 6.92 (d, J=8.7 Hz, 1H) ppm.

Step 4:3-(Difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoylchloride

To a solution of3-(difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid(170 mg, 0.464 mmol) and DMF (35 μL, 0.45 mmol) in dichloromethane (2mL) at 0° C. was added oxalyl chloride (70 μL, 0.80 mmol) dropwise. Themixture was stirred at room temperature for 20 minutes. Conversion wasmonitored by UPLC via test for morpholine adduct formation. The solventwas evaporated under reduced pressure to afford3-(difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoylchloride.

Step 5:N-(3-Carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(74)

To a solution of 5-amino-2-fluoro-benzamide (60 mg, 0.39 mmol) and DIEA(150 μL, 0.861 mmol) in THF (2 mL) at 0° C. was added a suspension of3-(difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoylchloride (150 mg, 0.390 mmol) in dichloromethane (1 mL). The reactionmixture was allowed to warm to room temperature and stirred for 16hours. The reaction mixture was partitioned between water anddichloromethane. The organic layer was washed with 1 M HCl (2×), driedover MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-50% ethyl acetate/hexanes) providedN-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(75 mg, 38%). ESI-MS m/z calc. 502.08, found 503.1 (M+1)+; retentiontime (Method B): 1.72 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.98 (s, 1H), 7.96 (dd, J=6.4, 2.8 Hz, 1H), 7.78-7.66 (m, 4H), 7.46(dq, J=7.7, 1.0 Hz, 2H), 7.42-7.10 (m, 4H), 6.89 (d, J=8.7 Hz, 1H) ppm.

Example 764-[[3-(Difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(83)

A microwave vial charged with4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Preparation 1, 99 mg, 0.30 mmol),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (2.4 mg, 0.007 mmol) and3-(difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid(prepared as described in Example 75, step 3, 100 mg, 0.273 mmol) in2-propanol (2 mL) was heated at 83° C. for 16 hours. The reactionmixture was cooled to room temperature and concentrated in vacuo. Thecrude material was taken up in dichloromethane and washed with 1 M HCl.The organic layer was dried over MgSO₄, filtered and concentrated invacuo. Silica gel chromatography (0-60% ethyl acetate/hexanes) provided4-[[3-(difluoromethyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(82 mg, 62%). ESI-MS m/z calc. 485.08, found 486.2 (M+1)+; retentiontime (Method B): 1.84 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.42 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.11(s, 1H), 7.83-7.71 (m, 2H), 7.66 (d, J=2.9 Hz, 1H), 7.46 (dq, J=7.8, 1.0Hz, 2H), 7.41-7.11 (m, 3H), 6.91 (d, J=8.7 Hz, 1H) ppm.

Example 774-[[2-fluoro-3-(trifluoromethoxy)-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (243)

Step 1:2-fluoro-3-(trifluoromethoxy)-6-[4-(trifluoromethoxy)phenoxy]benzoicAcid

A suspension of 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (400mg, 1.32 mmol), 4-(trifluoromethoxy)phenol (190 μL, 1.47 mmol) andcesium carbonate (950 mg, 2.92 mmol) in toluene (8 mL) was heated to100° C. and then copper (I) iodide (53 mg, 0.28 mmol) was added. Themixture was heated at 100° C. overnight. The reaction mixture was cooledto room temperature then acidified to pH 2 with 2 M HCl. The mixture wasextracted with ethyl acetate (2×100 mL). The organics were combined andwashed with water (2×100 mL), brine (100 mL), dried over MgSO₄, filteredand concentrated in vacuo to afford2-fluoro-3-(trifluoromethoxy)-6-[4-(trifluoromethoxy)phenoxy]benzoicacid (500 mg, 95%) as a brown gummy solid, which was used in the nextstep without purification.

Step 2: methyl4-[[2-fluoro-3-(trifluoromethoxy)-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of2-fluoro-3-(trifluoromethoxy)-6-[4-(trifluoromethoxy)phenoxy]benzoicacid (400 mg, 1.0 mmol) in DCM (6 mL) was added DMF (13 μL, 0.17 mmol)and dropwise oxalyl dichloride (420 μL, 4.82 mmol) and was stirred for 2hours. The reaction mixture was concentrated in vacuo to afford the acidchloride as a pale yellow oil. The residue was dissolved in DCM (6 mL)and added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate(275 mg, 1.81 mmol) and triethylamine (1.3 mL, 9.33 mmol) in DCM (6 mL)in an ice bath. The resulting mixture was stirred and warmed to roomtemperature overnight. The reaction mixture was concentrated in vacuoand purified by silica gel chromatography (ethyl acetate/heptane) toafford methyl4-[[2-fluoro-3-(trifluoromethoxy)-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(65 mg, 12%) as a clear waxy solid. ESI-MS m/z calc. 534.07, found 535.6(M+1)+; 533.6 (M−1)−; Retention time (Method F): 0.97 minutes (1.5minutes run). ¹H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.51 (d, J=5.5 Hz,1H), 8.14 (d, J=2.2 Hz, 1H), 7.94 (dd, J=5.6, 2.2 Hz, 1H), 7.21 (ddq,J=9.5, 8.4, 1.2 Hz, 1H), 7.14 (dtd, J=8.5, 2.3, 1.3 Hz, 2H), 7.06-6.94(m, 2H), 6.58 (dd, J=9.2, 1.8 Hz, 1H), 3.82 (s, 3H) ppm.

Step 3:4-[[2-fluoro-3-(trifluoromethoxy)-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(243)

Methyl4-[[2-fluoro-3-(trifluoromethoxy)-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(100 mg, 0.19 mmol) was dissolved in ammonia (5 mL of 7 M in methanol,35 mmol) and stirred at room temperature overnight. The reaction mixturewas concentrated in vacuo to afford4-[[2-fluoro-3-(trifluoromethoxy)-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(243, 58 mg, 50%). ESI-MS m/z calc. 519.07, found 520.3 (M+1)+;Retention time (Method E): 3.29 minutes (5 minutes run). ¹H NMR (400MHz, Chloroform-d) δ 10.10 (s, 1H), 8.42 (s, 2H), 8.13 (t, J=1.4 Hz,1H), 7.79 (d, J=4.5 Hz, 1H), 7.28 (ddd, J=9.4, 8.1, 1.2 Hz, 1H),7.13-7.07 (m, 2H), 7.04-6.98 (m, 2H), 6.62 (dd, J=9.2, 1.7 Hz, 1H), 4.92(d, J=4.6 Hz, 1H) ppm.

Example 78N-(2-Carbamoyl-5-methyl-4-pyridyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(144) andN-(2-Carbamoyl-5-methyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(143)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide

This compound was made in an analogous fashion to methyl4-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(Example 12, Step 4), except employing 2-bromo-5-methyl-pyridin-4-aminein the amide formation step. The yield of the desired product afterpurification was 282 mg (67%). ESI-MS m/z calc. 583.00, found 585.0(M+1)+; retention time (Method F): 1.14 minutes (1.5 minute run).

Step 2: Methyl4-[[3-Fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylateand methyl4-[[3-Methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate

(2-bromo-5-methyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(282 mg, 0.483 mmol) was dissolved in methanol (5 mL), and triethylamine(143 μL, 1.03 mmol) and Pd(dppf)Cl₂.DCM (80 mg, 0.0980 mmol) were added.Carbon monoxide was bubbled through the vigorously stirring reactionmixture for 5 minutes. The reaction mixture was then heated to 75° C.under carbon monoxide atmosphere for 7 hours. The reaction was cooled,then filtered through a pad of Celite eluting with methanol, andconcentrated in vacuo. Silica gel chromatography (30-80% ethylacetate/petroleum ether) provided a 1:1 mixture (378 mg) of methyl4-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate;ESI-MS m/z calc. 563.09, found 564.0 (M+1)⁺; retention time (Method F):1.02 minutes (1.5 minute run) and methyl4-[[3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate.ESI-MS m/z calc. 575.11, found 576.0 (M+1)+; retention time (Method F):1.01 minutes.

Step 3:N-(2-Carbamoyl-5-methyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(143) andN-(2-Carbamoyl-5-methyl-4-pyridyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(144)

A mixture of methyl4-[[3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(approximately 195 mg, 0.34 mmol), methyl4-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(approximately 189 mg, 0.34 mmol) and ammonia (9.4 mL of 4 M inmethanol, 37.6 mmol) was stirred at ambient temperature for 16 hours.SPM32 silica metal scavenger (150 mg) was added and the reaction wasstirred at ambient temperature for 15 minutes. The mixture was filteredand the filtrate was concentrated in vacuo. HPLC purification (37-100%acetonitrile/0.1% ammonium hydroxide) followed by SFC purification(Daicel Chiralpak AD-H column (250×10 mm, 5 μm particle), isocratic runof 15% methanol with 20 mM ammonia solution (anhydrous) (mobile phaseB). Mobile phase A=Supercritical carbon dioxide. Mobile phase B=Methanolwith 20 mM Ammonia. Flow rate=10 mL/min. Detection: UV @ 280 nm. Columntemperature=35° C.) provided:

143:N-(2-carbamoyl-5-methyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(83, 7.0 mg, 4%). ESI-MS m/z calc. 548.0931, found 549.0 (M+1)+;retention time (Method E): 3.23 minutes (5 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 10.73 (s, 1H), 8.49 (d, J=4.4 Hz, 2H), 8.26-8.05 (m, 2H),7.64 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.05 (ddd,J=8.9, 2.8, 1.3 Hz, 1H), 3.83 (s, 3H), 2.32 (s, 3H) ppm; and

144:N-(2-carbamoyl-5-methyl-4-pyridyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(82, 53.9 mg, 28%). ESI-MS m/z calc. 560.11304, found 561.0 (M+1)+;retention time (Method E): 3.19 minutes (5 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 10.67 (s, 1H), 8.58-8.42 (m, 2H), 8.10 (d, J=2.8 Hz, 1H),7.93 (s, 1H), 7.65 (d, J=2.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.27 (d,J=2.8 Hz, 1H), 7.05 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 4.04 (s, 3H), 3.83(s, 3H), 2.33 (s, 3H) ppm.

Example 79N-(6-Carbamoyl-3-pyridyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(203)

To a microwave vial was addedN-(6-carbamoyl-3-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(194, prepared as described in Example 12, 54 mg, 0.010 mmol) followedby sodium methoxide (1 mL of 0.5 M, 0.5 mmol). The reaction vial wassealed and heated at 80° C. overnight. The reaction mixture was cooled,treated with 2 drops of trifluoroacetic acid to quench and diluted withDMSO. HPLC purification (37-100% acetonitrile/0.1% ammonium hydroxide)providedN-(6-carbamoyl-3-pyridyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(8.5 mg, 14%). ESI-MS m/z calc. 546.10, found 547.1 (M+1)+; 545.0(M−1)−; retention time: 3.14 minutes (Method E). ¹H NMR (500 MHz, CDCl₃)δ 8.71 (d, J=2.5 Hz, 1H), 8.36-8.28 (m, 2H), 8.26 (d, J=8.4 Hz, 1H),7.91 (s, 1H), 7.71 (s, 1H), 7.26 (1H, obscured by solvent peak),6.98-6.90 (m, 2H), 5.52 (s, 1H), 4.10 (s, 3H), 3.87 (s, 3H) ppm.

Example 80N-(2-Carbamoyl-4-pyridyl)-3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(206)

Step 1: Ethyl4-[[3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate

Methyl4-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(prepared as described in Example 12, Step 4, 190 mg, 0.346 mmol) wasdissolved in ethanol (2.0 mL, 35 mmol) and treated with sodium ethoxide(35 mg, 0.51 mmol). The reaction mixture was heated at 75° C. for 72hours. Additional sodium ethoxide (35 mg, 0.5143 mmol) was added and thereaction heated for an additional 72 hours. The reaction mixture wasconcentrated in vacuo to provide crude ethyl4-[[3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(150 mg, 74% crude yield). ESI-MS m/z calc. 589.13, found 590.0 (M+1)+;retention time (Method F): 1.02 minutes (1.5 minute run).

Step 2:N-(2-Carbamoyl-4-pyridyl)-3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(206)

Ethyl4-[[3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(150 mg, 0.254 mmol) was dissolved in an ammonia solution (4.1 mL of 7M, 28.70 mmol) and was stirred for 72 hours under N₂. The reactionmixture was concentrated in vacuo and purified by HPLC (0-100%acetonitrile/0.1% ammonium hydroxide) to provideN-(2-carbamoyl-4-pyridyl)-3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(45 mg, 31%) as a white solid. ESI-MS m/z calc. 560.11, found 561.0(M+1)+; retention time (Method E): 3.4 minutes (5 minute run). ¹H NMR(500 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.57 (dd, J=5.5, 0.7 Hz, 1H), 8.32(dd, J=2.2, 0.7 Hz, 1H), 8.11 (d, J=2.9 Hz, 1H), 7.97 (s, 1H), 7.81 (dd,J=5.5, 2.2 Hz, 1H), 7.67 (d, J=2.8 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H),7.30-7.08 (m, 1H), 7.11-6.89 (m, 1H), 4.19 (q, J=7.0 Hz, 2H), 3.80 (s,3H), 1.28 (t, J=7.0 Hz, 3H) ppm.

Example 81N-(2-Carbamoyl-5-methyl-4-pyridyl)-3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(210)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide

N-(2-Bromo-5-methyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(prepared as described in Example 83, Step 1, 180 mg, 0.308 mmol) wasdissolved in ethanol (1.8 mL) and treated with sodium ethoxide (31 mg,0.4555 mmol). The reaction was heated at 75° C. for 72 hours, thentreated with additional sodium ethoxixde (31 mg, 0.4555 mmol) and heatedfor an additional 72 hours. The reaction mixture was concentrated invacuo to afford crudeN-(2-bromo-5-methyl-4-pyridyl)-3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide.ESI-MS m/z calc. 609.03, found 612.0 (M+1)+; retention time (Method F):1.13 minutes (1.5 minute run).

Step 2: Methyl4-[[3-Ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate

N-(2-bromo-5-methyl-4-pyridyl)-3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(150 mg, 0.246 mmol) was dissolved in methanol (3 mL), and triethylamine(80 μL, 0.5740 mmol) and Pd(dppf)Cl₂.DCM (42 mg, 0.051 mmol) were added.Carbon monoxide was bubbled through the vigorously stirring reactionmixture for 5 minutes. The reaction mixture was heated at 75° C. undercarbon monoxide atmosphere for 16 hours. The reaction was cooled,filtered through a pad of Celite eluting with methanol and concentratedin vacuo. The residue was purified by silica gel chromatography (30-80%ethyl acetate/petroleum ether) to provide methyl4-[[3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(40 mg, 28%) as a pale yellow oil. ESI-MS m/z calc. 589.13, found 590.0(M+1)+; retention time (Method F): 0.98 minutes (1.5 minute run).

Step 3:N-(2-Carbamoyl-5-methyl-4-pyridyl)-3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(210)

A solution of methyl4-[[3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(40 mg, 0.068 mmol) in ammonia (1.5 mL of 7 M in methanol, 10.50 mmol)was stirred at room temperature for 48 hours. The reaction mixture wasconcentrated in vacuo and purified by HPLC (37-100% acetonitrile/0.1%ammonium hydroxide) to provideN-(2-carbamoyl-5-methyl-4-pyridyl)-3-ethoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(19 mg, 49%). ESI-MS m/z calc. 574.13, found 575.0 (M+1)+; retentiontime (Method E): 3.4 minutes (5 minute run). ¹H NMR (500 MHz, DMSO-d6) δ10.63 (s, 1H), 8.48 (s, 2H), 8.06 (s, 1H), 7.92 (s, 1H), 7.60 (s, 1H),7.36 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.11-6.98 (m, 1H), 4.26(q, J=7.0 Hz, 2H), 3.83 (s, 3H), 2.31 (s, 3H), 1.34 (t, J=7.0 Hz, 3H)ppm.

Example 824-[[3-Chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(70)

Step 1: 6-Bromo-3-chloro-2-fluoro-benzoic Acid

To a solution of 6-bromo-3-chloro-2-fluoro-benzaldehyde (1.00 g, 4.211mmol) in a mixture of tert-BuOH (7 mL) and water (5 mL) was added sodiumdihydrogen phosphate hydrate (0.600 g, 5.00 mmol) and 2-methyl-2-butene(9.5 mL of 2 M, 19 mmol). Sodium chlorite (0.600 g, 5.307 mmol) was thenadded in one portion and the reaction stirred for 2 hours. The reactionmixture was acidified using 1M HCl, and partitioned with ethyl acetate.The organic layer was dried over MgSO₄, filtered and concentrated invacuo to afford 6-bromo-3-chloro-2-fluoro-benzoic acid (0.900 g, 84%) asa white solid. ESI-MS m/z calc. 251.90, found 209.0 (M+1)+ (mass of thedecarboxylation fragment); retention time (Method F): 0.36 minutes (1.5minute run).

Step 2: 3-Chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic Acid

To a pressure flask was added 6-bromo-3-chloro-2-fluoro-benzoic acid(1.00 g, 3.95 mmol), 4-(trifluoromethoxy)phenol (0.705 g, 3.96 mmol),Cs₂CO₃ (1.29 g, 3.94 mmol) and toluene (12 mL). The reaction mixture wasbubbled with N₂ for 10 minutes, and then copper (I) iodide (0.375 g,1.97 mmol) added. The flask was flushed with N₂, capped, and heated at100° C. with vigorous stirring for 1 hour. The mixture was allowed tocool, then diluted with ethyl acetate and water. The water layer wasacidified with HCl and the product was extracted into ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-5%methanol/dichloromethane) provided3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid (0.820 g,59%) as a white solid. ESI-MS m/z calc. 349.9969, found 351.0 (M+1)+;retention time (Method B): 1.82 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 14.02 (s, 1H), 7.69 (t, J=8.7 Hz, 1H), 7.46-7.38 (m, 2H),7.20-7.13 (m, 2H), 6.92 (dd, J=9.0, 1.5 Hz, 1H) ppm.

Step 3: 3-Chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoylchloride

To a solution of3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid (300 mg,0.856 mmol) and DMF (23 μL, 0.29 mmol) in dichloromethane (4 mL) at 0°C. was added oxalyl chloride (164 mg, 113 μL, 1.30 mmol) dropwise. Themixture was stirred at room temperature for 30 minutes. Conversion wasmonitored by UPLC via test for morpholine adduct formation. The solventwas evaporated in vacuo to afford3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl chloride.

Step 4:4-[[3-Chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(70)

To a solution of 4-aminopyridine-2-carboxamide (37 mg, 0.27 mmol) andDIEA (94 μL, 0.54 mmol) in THF (1 mL) at 0° C. was added a solution of3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl chloride (100mg, 0.271 mmol) in THF (1.0 mL) and dichloromethane (1.0 mL) at 0° C.The reaction mixture was allowed to warm to room temperature and stirredfor 16 hours. The mixture was quenched with water and extracted withdichloromethane. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel column chromatography (0-60% ethylacetate/hexanes) provided4-[[3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(15 mg, 11%). ESI-MS m/z calc. 469.05, found 470.1 (M+1)+; retentiontime (Method B): 1.74 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.39 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H), 8.10(s, 1H), 7.77 (dd, J=5.7, 2.3 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.66 (d,J=2.8 Hz, 1H), 7.41 (dq, J=7.8, 1.0 Hz, 2H), 7.28-7.21 (m, 2H), 6.93(dd, J=9.0, 1.4 Hz, 1H) ppm.

Example 83N-(3-Carbamoyl-4-fluoro-phenyl)-3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(73)

This compound was made in an analogous fashion to Example 82 exceptemploying 5-amino-2-fluoro-benzamide in the amide formation step (Step4). The yield of the desired product after purification was 57 mg (43%).ESI-MS m/z calc. 486.04, found 487.1 (M+1)+; retention time (Method B):1.76 minutes (3 minute run). ¹H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H),7.92 (dd, J=6.4, 2.8 Hz, 1H), 7.74-7.64 (m, 4H), 7.41 (d, J=8.7 Hz, 2H),7.29-7.18 (m, 3H), 6.89 (dd, J=9.1, 1.4 Hz, 1H) ppm.

Example 84N-(3-Carbamoyl-4-fluoro-phenyl)-1,1-difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carboxamide(190)

Step 1: 2-bromo-6-(4-(trifluoromethoxy)phenoxy)benzaldehyde

A mixture of 2-bromo-6-fluorobenzaldehyde (10.2 g, 50 mmol),4-(trifluoromethoxy)phenol (6.5 mL, 50 mmol), K₂CO₃ (13.8 g, 100 mmol)in DMF (100 mL) was purged with N₂ and heated at 70° C. for 2 hours.Water (300 mL) was added and the reaction mixture was extracted withdiethyl ether (2×100 mL). The combined organics were washed with brine,dried over Na₂SO₄, concentrated and the residue was purified by silicagel column chromatography using dichloromethane to afford2-bromo-6-(4-(trifluoromethoxy)phenoxy)benzaldehyde (16.2 g, 89%) as ayellow oil. ESI-MS m/z calc. 361.96, found 363.0 (M+1)+; retention time(Method G): 3.49 minutes (6 minute run time).

Step 2: (E)-tert-butyl3-(2-formyl-3-(4-(trifluoromethoxy)phenoxy)phenyl)acrylate

A mixture of 2-bromo-6-(4-(trifluoromethoxy)phenoxy)benzaldehyde (15.0g, 41.5 mmol), palladium acetate (466 mg, 2.08 mmol),tri-o-tolylphosphine (1.26 g, 4.15 mmol) and tert-butyl acrylate (9.0mL, 62 mmol) in triethylamine (17 mL) and toluene (85 mL) was heated atreflux for 2.5 hours. Water (100 mL) and 1 M aqueous HCl (100 mL) wereadded and the reaction was extracted with hexane (100 mL) and ethylacetate (100 mL). The combined organics was dried over Na₂SO₄,concentrated in vacuo and purified by silica gel column chromatography(0-30% ethyl acetate/hexanes) to afford (E)-tert-butyl3-(2-formyl-3-(4-(trifluoromethoxy)phenoxy)phenyl)acrylate (9.02 g, 53%)as a yellow solid. ESI-MS m/z calc. 408.12, found 408.8 (M+1)+;retention time (Method G): 4.07 minutes (6 minute run).

Step 3:(E)-2-(3-tert-Butoxy-3-oxoprop-1-enyl)-6-(4-(trifluoromethoxy)phenoxy)benzoicAcid

To a mixture of (E)-tert-butyl3-(2-formyl-3-(4-(trifluoromethoxy)phenoxy)phenyl)acrylate (7.52 g, 18.4mmol) and 2-methyl-2-butene (23.5 mL, 221 mmol) in tert-BuOH (235 mL)was added a solution of sodium chlorite (11.1 g, 123 mmol) and monobasicsodium phosphate (14.0 g, 101 mmol) in water (80 mL) over 30 minutes.The reaction mixture was stirred for 1 hour at room temperature and thendiluted with 2:1 water:brine solution (750 mL). The mixture wasextracted with ethyl acetate (750 mL). The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo to afford(E)-2-(3-tert-butoxy-3-oxoprop-1-enyl)-6-(4-(trifluoromethoxy)phenoxy)benzoicacid (7.88 g, 101%) as a yellow solid. Retention time (Method G): 3.59minutes (6 minute run).

Step 4: (E)-methyl2-(3-tert-butoxy-3-oxoprop-1-enyl)-6-(4-(trifluoromethoxy)phenoxy)benzoate

To(E)-2-(3-tert-butoxy-3-oxoprop-1-enyl)-6-(4-(trifluoromethoxy)phenoxy)benzoicacid (7.88 g, 18.4 mmol) and K₂CO₃ (2.54 g, 18.4 mmol) in acetone (75mL) was added methyl iodide (3.4 mL, 55 mmol) and the reaction washeated at 40° C. for 45 minutes. The reaction was cooled, diluted withethyl acetate (450 mL) and washed with water and brine (2×). The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo toafford (E)-methyl2-(3-tert-butoxy-3-oxoprop-1-enyl)-6-(4-(trifluoromethoxy)phenoxy)benzoate(7.36 g, 91%) as an amber oil. Retention time (Method G): 4.06 minutes(6 minute run).

Step 5: Methyl 2-(3tert-butoxy-3-oxopropyl)-6-4-trifluoromethoxy)phenoxy)benzoate

To (E)-methyl2-(3-tert-butoxy-3-oxoprop-1-enyl)-6-(4-(trifluoromethoxy)phenoxy)benzoate(7.36 g, 16.8 mmol) and 10% palladium on carbon (2 g) was added methanol(75 mL), and the reaction was heated at 40° C. under hydrogen atmospherefor 3 hours. The reaction mixture was filtered through a pad of Celiteand rinsed with methanol. The filtrate was concentrated in vacuo toafford methyl2-(3-tert-butoxy-3-oxopropyl)-6-(4-(trifluoromethoxy)phenoxy)benzoate(6.70 g, 91%) as an amber oil. ESI-MS m/z calc. 440.14, found 441.3(M+1)+; retention time (Method H): 4.19 minutes (12 minute run).

Step 6:3-(2-(methoxycarbonyl)-3-(4-(trifluoromethoxy)phenoxy)phenyl)propanoicAcid

To 2-(3-tert-butoxy-3-oxopropyl)-6-(4-(trifluoromethoxy)phenoxy)benzoate(6.70 g, 15.2 mmol) in dichloromethane (30 mL) was added trifluoroaceticacid (10 mL, 152 mmol). The reaction was stirred for 18 hours at roomtemperature before the mixture was concentrated twice with1,2-dichloroethane (2×15 mL). The crude reaction mixture was purifiedvia silica gel column chromatography (0-60% ethyl acetate/hexanes) toafford3-(2-(methoxycarbonyl)-3-(4-(trifluoromethoxy)phenoxy)phenyl)propanoicacid (5.14 g, 88%) as a white solid. ESI-MS m/z calc. 384.08, found384.9 (M+1)+); retention time (Method G): 3.16 minutes (6 minute run).

Step 7: Methyl2-(3-chloro-3-oxopropyl)-6-(4-(trifluoromethoxy)phenoxy)benzoate

To a solution of3-(2-(methoxycarbonyl)-3-(4-(trifluoromethoxy)phenoxy)phenyl)propanoicacid (4.17 g, 10.8 mmol) in dichloromethane (44 mL) was added oxalylchloride (1.8 mL, 21.7 mmol) followed by DMF (5 μL). The reactionmixture was stirred for 3 hours at room temperature and thenconcentrated twice with 1,2-dichloroethane (10 mL) to afford methyl2-(3-chloro-3-oxopropyl)-6-(4-(trifluoromethoxy)phenoxy)benzoate (4.24g, 97%) as an oil, which was used directly in the next step.

Step 8: methyl1-oxo-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylate

A suspension of aluminum trichloride (2.96 g, 22.2 mmol) indichloromethane (100 mL) was cooled to 0° C. and a solution of methyl2-(3-chloro-3-oxopropyl)-6-(4-(trifluoromethoxy)phenoxy)benzoate (3.57g, 8.87 mmol) in dichloromethane (17 mL) was added over 5 minutes. Thereaction mixture was stirred for 20 minutes then poured into ice water(200 mL). The mixture was extracted with dichloromethane (2×100 mL), andthe organics were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (0-50% ethylacetate/hexanes) to afford methyl1-oxo-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylate(2.76 g, 85%) as an off-white solid. ESI-MS m/z calc. 366.07, found366.7 (M+1)+; retention time (Method G): 3.28 minutes (6 minute run). ¹HNMR (250 MHz, DMSO-d6) δ (ppm): 2.62-2.76 (m, 2H) 3.14-3.28 (m, 2H) 3.80(s, 3H) 7.06 (d, J=8.35 Hz, 1H) 7.19 (d, J=9.01 Hz, 2H) 7.44 (d, J=9.01Hz, 2H) 7.80 (d, J=8.46 Hz, 1H) ppm.

Step 9: Methyl5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolane]-4-carboxylate

A solution of methyl1-oxo-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylate(1.59 g, 4.35 mmol) and ethane-1,2-dithiol (550 uL, 6.52 mmol) indichloromethane (17 mL) was cooled in an ice bath and boron trifluorideetherate (2.0 mL, 17 mmol) was added. The reaction mixture was stirredfor 18 hours at room temperature. 2 M aqueous NaOH (25 mL) was added andthe mixture was extracted with dichloromethane (2×25 mL). The combinedorganic layers were dried over Na₂SO₄, concentrated in vacuo andpurified by silica gel chromatography (0-30% ethyl acetate/hexanes) toafford methyl5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolane]-4-carboxylate(1.57 g, 82%) as a white solid. ESI-MS m/z calc. 442.05, found 442.8(M+1)+; retention time (Method G): 3.98 minutes (6 minute run).

Step 10: Methyl2-bromo-1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylate

To a solution of dibromantin (2.9 g, 10.2 mmol) in dichloromethane (12mL) at −78° C. was added 70% HF/pyridine (3.0 mL, 1173 mmol) and themixture was stirred for 30 minutes. A solution of methyl5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolane]-4-carboxylate(1.13 g, 2.55 mmol) in dichloromethane (2.5 mL) was added dropwise.After 1 hour the dry ice bath was removed and the reaction was allowedto warm to room temperature, and then poured onto a mixture of 2 Maqueous NaOH (50 mL) and saturated aqueous sodium bisulfite solution(7.5 mL). The mixture was basified with the addition of 2 M aqueous NaOHand extracted with dichloromethane (2×50 mL). The combined organic layerwas dried over Na₂SO₄, concentrated in vacuo and purified by silica gelchromatography (0-10% ethyl acetate/hexanes) to afford methyl2-bromo-1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylate(779 mg, 47%) as a colorless oil. Retention time (Method G): 3.30minutes (6 minute run).

Step 11: Methyl1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-1H-indene-4-carboxylate

To a solution of methyl2-bromo-1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylate(779 mg, 1.67 mmol) in dichloromethane (6 mL) was added2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.38 mL, 2.50 mmol).After stirring for 30 minutes at room temperature, 2 M aqueous HCl (25mL) was added. The mixture was extracted with dichloromethane (2×25 mL).The combined organic layers were dried over Na₂SO₄, concentrated invacuo and purified by silica gel chromatography (0-50%dichloromethane/hexanes) to afford methyl1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-1H-indene-4-carboxylate(595 mg, 92%) as a yellow oil. Retention time (Method G): 3.15 minutes(6 minute run).

Step 12: Methyl1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylate

To a solution of methyl1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-1H-indene-4-carboxylate(484 mg, 1.25 mmol) in methanol (15 mL) was added 10% palladium oncarbon (100 mg) and the reaction mixture was hydrogenated in a Parrshaker at 60 PSI for 18 hours. The mixture was filtered over Celite padand the filtrate was concentrated in vacuo. Silica gel chromatography(0-40% dichloromethane/hexanes) provided methyl1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylate(461 mg, 91%) as a colorless oil. ESI-MS m/z calc. 388.07, found 389.0(M+1)+; retention time (Method G): 3.71 minutes (6 minute run).

Step 13: 1,1-Difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carboxylicAcid

A mixture of methyl1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylate(393 mg, 1.01 mmol), lithium hydroxide hydrate (168 mg, 4.00 mmol), THF(2 mL), methanol (2 mL) and water (2 mL) was stirred at room temperaturefor 4 hours. The reaction was diluted with saturated NH₄Cl (50 mL) andextracted with ethyl acetate (2×25 mL). The combined organic layers wereconcentrated to provide1,1-difluoro-5-(4-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-indene-4-carboxylicacid (417 mg, 96%) as an off-white solid. ESI-MS m/z calc. 374.06, found374.9 (M+1)+; retention time (Method G): 3.25 minutes (6 minute run). ¹HNMR (250 MHz, DMSO-d6) δ (ppm): 2.63 (dd, J=13.95, 6.81 Hz, 2H) 3.09(bs, 2H) 6.88-7.15 (m, 3H) 7.36 (d, J=8.46 Hz, 2H) 7.59 (d, J=7.80 Hz,1H) ppm.

Step 14: 1,1-Difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carbonylchloride

To a solution of1,1-difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carboxylic acid(272 mg, 0.726 mmol) and DMF (20 μL, 0.26 mmol) in dichloromethane (3mL) at 0° C. was added oxalyl chloride (400 μL, 4.59 mmol) dropwiseunder N₂ atmosphere. The ice bath was removed after 10 minutes and thereaction was stirred at room temperature for 30 minutes. Conversion wasmonitored by UPLC via test for piperidine adduct formation. The solventwas evaporated under reduced pressure to afford1,1-difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carbonyl chloride.

Step 15:N-(3-Carbamoyl-4-fluoro-phenyl)-1,1-difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carboxamide(190)

A slurry of 5-amino-2-fluoro-benzamide (42 mg, 0.27 mmol) indichloromethane (1 mL) and DIEA (63 μL, 0.36 mmol) was cooled to 0° C. Aslurry of cold1,1-difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carbonyl chloride(71 mg, 0.18 mmol) in dichloromethane (1 mL) was added dropwise to thestirring amine solution. The reaction mixture was stirred at 0° C. for10 minutes then allowed to warm to room temperature over 2 hours. Thereaction was concentrated in vacuo and purified by HPLC (10-99%acetonitrile/5 mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-1,1-difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carboxamide(42.5 mg, 46%). ESI-MS m/z calc. 510.10, found 511.0 (M+1)+; retentiontime (Method C): 2.51 minutes (5 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.69 (s, 1H), 7.96 (dd, J=6.4, 2.8 Hz, 1H), 7.77-7.70 (m, 1H),7.70-7.62 (m, 3H), 7.55-7.31 (m, 2H), 7.29-7.17 (m, 3H), 7.01 (d, J=8.5Hz, 1H), 3.21-2.98 (m, 2H), 2.78-2.59 (m, 2H) ppm.

Example 854-[[1,1-Difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carbonyl]amino]pyridine-2-carboxamide(191)

This compound was made in an analogous fashion to Example 84 exceptemploying 4-aminopyridine-2-carboxamide in the amide formation step(Step 15). The yield of the desired product after purification was 30 mg(41%). ESI-MS m/z calc. 493.1061, found 494.0 (M+1)+; retention time(Method C): 2.46 minutes (5 minute run). ¹H-NMR (400 MHz, DMSO-d6) δ11.15 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.11 (d,J=2.8 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.71 (dd, J=8.5, 1.5 Hz,1H), 7.66 (d, J=2.9 Hz, 1H), 7.41 (dd, J=9.2, 1.0 Hz, 2H), 7.27-7.19 (m,2H), 7.02 (d, J=8.5 Hz, 1H), 3.19-3.06 (m, 2H), 2.68 (tt, J=13.3, 7.0Hz, 2H) ppm.

Example 865-[[1,1-Difluoro-5-[4-(trifluoromethoxy)phenoxy]indane-4-carbonyl]amino]pyridine-2-carboxamide(192)

This compound was made in an analogous fashion to Example 84 exceptemploying 5-aminopyridine-2-carboxamide in the amide formation step(Step 15). The yield of the desired product after purification was 34 mg(43%). ESI-MS m/z calc. 493.11, found 494.0 (M+1)+; retention time(Method C): 2.45 minutes (5 minute run). ¹H-NMR (400 MHz, DMSO-d6) δ11.06 (s, 1H), 8.82 (dd, J=2.5, 0.7 Hz, 1H), 8.24 (dd, J=8.6, 2.5 Hz,1H), 8.06-7.98 (m, 2H), 7.71 (dd, J=8.5, 1.5 Hz, 1H), 7.56 (d, J=2.8 Hz,1H), 7.41 (dt, J=8.0, 1.0 Hz, 2H), 7.27-7.16 (m, 2H), 7.05 (d, J=8.4 Hz,1H), 3.17-3.07 (m, 2H), 2.68 (tt, J=14.2, 6.9 Hz, 2H) ppm.

Example 874-[[2,4-Dichloro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(180)

Step 1: 2,4-Dichloro-6-fluoro-benzoic Acid

To a solution of 2,4-dichloro-6-fluoro-benzaldehyde (1.00 g, 5.18 mmol),2-methyl-2-butene (1.82 g, 2.74 mL, 25.9 mmol) and sodium dihydrogenphosphate hydrate (2.14 g, 15.5 mmol) in tert-BuOH (5 mL)/acetonitrile(3.25 mL)/water (5 mL) at 0° C. was added sodium chlorite (1.41 g, 15.5mmol) and the reaction mixture stirred at 0° C. for 1 hour. The reactionmixture was acidified with 1N HCl and extracted with ethyl acetate. Theorganic layer was washed with 1N HCl and brine, dried over Na₂SO₄,filtered and concentrated. Trituration with 20% diethyl ether/hexane andfiltration provided 2,4-dichloro-6-fluoro-benzoic acid (700 mg, 65%) asa white solid. ¹H NMR (400 MHz, DMSO-d6) δ 14.29 (br s, 1H), 7.70-7.63(m, 2H) ppm.

Step 2: 2,4-Dichloro-6-fluoro-benzoyl chloride

To 2,4-dichloro-6-fluoro-benzoic acid (5.10 g, 24.4 mmol) and DMF (173μL, 2.23 mmol) in dichloromethane (50 mL) at 0° C. was added oxalylchloride (10.2 mL, 117 mmol) dropwise. The mixture was stirred at roomtemperature for 5 hours under N₂ atmosphere. Conversion was monitored byUPLC via test for morpholine adduct formation. The solvent wasevaporated under reduced pressure to afford2,4-dichloro-6-fluoro-benzoyl chloride.

Step 3: 4-[(2,4-Dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide

To 4-aminopyridine-2-carboxamide (1.51 g, 11.0 mmol) and DIEA (4.8 mL,27.5 mmol) in 1-methyl-pyrrolidin-2-one (25 mL) cooled at 0° C. wasadded a solution of 2,4-dichloro-6-fluoro-benzoyl chloride (2.5 g, 11mmol) in dichloromethane (12.5 mL) dropwise. The reaction was stirred atroom temperature for 16 hours. Water was added to the reaction mixtureand the resulting precipitate was filtered and dried to obtain4-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (1.05 g,29%). ESI-MS m/z calc. 327.00, found 328.1 (M+1)+; retention time(Method B): 1.16 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.42 (s, 1H), 8.58 (d, J=5.4 Hz, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.12 (d,J=2.8 Hz, 1H), 7.88-7.51 (m, 4H) ppm.

Step 4:4-[[2,4-Dichloro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(180)

To 4-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (45mg, 0.14 mmol) in DMF (1 mL) was added 4-(trifluoromethoxy)phenol (24mg, 18 μL, 0.14 mmol) followed by K₂CO₃ (57 mg, 0.41 mmol). The reactionwas heated at 80° C. for 30 minutes. HPLC purification (1-99%acetonitrile/5 mM HCl) provided4-[[2,4-dichloro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(38 mg, 57%). ESI-MS m/z calc. 485.02, found 485.85 (M+1)+; retentiontime (Method B): 1.82 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.36 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.28 (d, J=2.1 Hz, 1H), 8.12(d, J=2.7 Hz, 1H), 7.78 (dd, J=5.5, 2.2 Hz, 1H), 7.68 (s, 1H), 7.67 (d,J=1.8 Hz, 1H), 7.43 (dd, J=9.2, 1.0 Hz, 2H), 7.26 (d, J=9.1 Hz, 2H),7.13 (d, J=1.8 Hz, 1H) ppm. ¹⁹F NMR (376 MHz, DMSO-d6) δ −57.13 ppm.

Example 885-[[2,4-Dichloro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(184)

Step 1: 5-[(2,4-Dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide

This compound was made in an analogous fashion to Example 87, step 3,except employing 5-aminopyridine-2-carboxamide in the amide formationstep. The yield of the desired product after purification was 1.2 g(33%). ESI-MS m/z calc. 327.00, found 328.1 (M+1)+; retention time(Method B): 1.16 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.34 (s, 1H), 8.88-8.82 (m, 1H), 8.29 (dd, J=8.5, 2.5 Hz, 1H),8.12-8.01 (m, 2H), 7.76 (dq, J=4.2, 2.0 Hz, 2H), 7.58 (s, 1H) ppm.

Step 2:5-[[2,4-Dichloro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(184)

To a solution of5-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (44 mg,0.13 mmol) in DMF was added 4-(trifluoromethoxy)phenol (24 mg, 17 μL,0.13 mmol) followed by K₂CO₃ (56 mg, 0.40 mmol). The reaction was heatedat 80° C. for 1 hour. The reaction was diluted with DMSO (0.5 mL),filtered, and purified by HPLC (1-99% acetonitrile/5 mM HCl) to provide5-[[2,4-dichloro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(36 mg, 53%). ESI-MS m/z calc. 485.02, found 485.8 (M+1)+; retentiontime (Method B): 1.81 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.23 (s, 1H), 8.86 (dd, J=2.5, 0.7 Hz, 1H), 8.27 (dd, J=8.6, 2.5 Hz,1H), 8.13-7.99 (m, 2H), 7.61-7.48 (m, 2H), 7.27 (d, J=8.8 Hz, 1H), 7.19(d, J=2.8 Hz, 1H), 7.00 (m, 1H) 6.76 (d, J=1.8 Hz, 1H) ppm.

Example 89N-(3-Carbamoyl-4-fluoro-phenyl)-6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(103)

Step 1: Methyl6-isopropenyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

A mixture of methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(prepared as described in Example 65, Step 1, 12.0 g, 28.4 mmol) andPd(dppf)Cl₂.DCM (1.86 g, 2.28 mmol) was suspended in anhydrousacetonitrile (120 mL) under a N₂ atmosphere. Isopropenylboronic acidpinacol ester (4.93 g, 28.5 mmol) was added to the reaction mixturefollowed by an aqueous K₂CO₃ (29 mL of 2 M, 57 mmol). The reactionmixture was heated at 80° C. for 6 hours. The mixture was cooled,partitioned between water and dichloromethane, and the layers separated.The aqueous layer was extracted with additional dichloromethane (2×),and the combined organics were dried over Na₂SO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-25% ethylacetate/hexanes) provided methyl6-isopropenyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(8.1 g, 74%) as a white solid. ESI-MS m/z calc. 383.10, found 384.1(M+1)+; retention time (Method A): 0.69 minutes (1 minute run).

Step 2: Methyl6-acetyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

Methyl6-isopropenyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(4.0 g, 10 mmol) was dissolved in THF (20 mL)/acetone (20 mL) and thenwater (20 mL) was added. The solution was cooled to 0° C. then treatedwith trichlororuthenium hydrate (150 mg, 0.665 mmol) followed byportionwise addition of sodium periodate (9.0 g, 42 mmol). The coolingbath was removed and the reaction was allowed to warm to roomtemperature over 1 hour. The reaction mixture was filtered through a padof Celite and the filter cake was rinsed with dichloromethane. Thefiltrate was then diluted with water and the layers separated. Theaqueous layer was extracted dichloromethane (2×) and the combinedorganics were dried over Na₂SO₄, filtered and concentrated in vacuo.Silica gel chromatography (0-30% ethyl acetate/hexanes) provided methyl6-acetyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(3.1 g, 76%) as a white solid. ESI-MS m/z calc. 385.08, found 386.1(M+1)+; retention time (method A): 0.70 minutes (1 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 9.01 (d, J=0.4 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H),7.33 (d, J=2.6 Hz, 1H), 7.09 (ddq, J=8.8, 2.4, 1.2 Hz, 1H), 6.99 (d,J=0.4 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 2.60 (s, 3H) ppm.

Step 3: Methyl6-(1-hydroxy-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

Methyl6-acetyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(1.56 g, 4.05 mmol) was dissolved in anhydrous THF (40 mL) under N₂atmosphere and the solution cooled to −78° C. A solution ofmethylmagnesium bromide (1.5 mL of 3 M in THF, 4.500 mmol) was thenadded dropwise. The reaction was stirred for an additional 10 minutesand then allowed to warm to room temperature over 2 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution and dilutedwith ethyl acetate. The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×). The combined organics were dried overNa₂SO₄, filtered and concentrated in vacuo. Silica gel chromatography(0-60% ethyl acetate/hexanes) provided methyl6-(1-hydroxy-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(590 mg, 36%). ESI-MS m/z calc. 401.11, found 402.2 (M+1)+; retentiontime (Method A): 0.56 minutes (1 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 8.81 (s, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.06(ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.88 (s, 1H), 5.26 (s, 1H), 3.84 (s, 3H),3.77 (s, 3H), 1.35 (s, 6H) ppm.

Step 4: Methyl6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

Methyl6-(1-hydroxy-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(574 mg, 1.43 mmol) was dissolved in anhydrous dichloromethane (6 mL)under N₂ atmosphere and cooled to −78° C. Deoxo-fluor (320 μL, 1.74mmol) as a solution in dichloromethane (1.2 mL) was then added dropwiseto the reaction mixture. The reaction mixture was stirred for 5 minutesthen allowed to warm to room temperature and stirred for 30 minutes. Thereaction was quenched with saturated aqueous NaHCO₃ solution andextracted with dichloromethane (2×). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-20% ethyl acetate/hexanes) provided methyl6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(375 mg, 65%). ESI-MS m/z calc. 403.10, found 404.2 (M+1)+; retentiontime (Method A): 0.75 minutes (1 minute run).

Step 5:6-(1-Fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicAcid

Methyl6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(375 mg, 0.930 mmol) was dissolved in methanol (1.5 mL)/THF (1 mL) atroom temperature and solution of NaOH (200 mg, 5.00 mmol) in water (1mL) was then added. The reaction mixture was stirred at room temperaturefor 1 hour. The solvents were removed in vacuo and the resulting whiteslurry was dissolved in water and cooled to 0° C. The solution wastreated with 6 M aqueous HCl until pH2. The resulting white suspensionwas filtered and the filter cake washed with water. The filter cake wasthen dried in a desiccator filled with DrieRite under high vacuum toprovide6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (285 mg, 79%) as a white solid. ESI-MS m/z calc. 389.09, found390.1 (M+1)+; retention time (Method A): 0.65 minutes (1 minute run).

Step 6:N-(3-Carbamoyl-4-fluoro-phenyl)-6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(103)

A mixture of6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (142 mg, 0.365 mmol), 5-amino-2-fluoro-benzamide (56 mg, 0.37mmol), HATU (140 mg, 0.368 mmol) and 4-methylmorpholine (111 mg, 1.10mmol) in DMF (1.5 mL) was stirred at room temperature for 20 minutes.The reaction mixture was partitioned between ethyl acetate and water.The layers were separated and the organic layer was washed with asaturated aqueous sodium chloride solution (2×). The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-60% ethyl acetate/hexanes) providedN-(3-carbamoyl-4-fluoro-phenyl)-6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(134 mg, 69%). ESI-MS m/z calc. 525.13, found 526.2 (M+1)+; retentiontime (method B): 1.71 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.65 (s, 1H), 8.70 (d, J=1.0 Hz, 1H), 8.03 (dd, J=6.4, 2.8 Hz, 1H),7.83 (ddd, J=9.0, 4.4, 2.8 Hz, 1H), 7.70 (d, J=14.6 Hz, 2H), 7.49 (d,J=8.8 Hz, 1H), 7.34-7.23 (m, 2H), 7.10 (ddt, J=7.7, 2.7, 1.3 Hz, 1H),6.64 (d, J=1.5 Hz, 1H), 3.79 (s, 3H), 1.61 (d, J=22.3 Hz, 6H) ppm. ¹⁹FNMR (376 MHz, DMSO-d6) δ −56.86, −119.01 (dt, J=8.9, 5.5 Hz),−140.24-−143.39 (m) ppm.

Example 90N-(2-Carbamoyl-4-pyridyl)-6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(104)

To a pressure vial were added6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (prepared as described in Example 95, Step 5, 143 mg, 0.367 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Preparation 1, 121 mg, 0.368 mmol) andtris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (3.9 mg, 0.011 mmol) and2-propanol (1.4 mL). The reaction vessel was sealed and stirred at 80°C. for 20 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. Silica gel chromatography (0-50% ethylacetate/dichloromethane) providedN-(2-carbamoyl-4-pyridyl)-6-(1-fluoro-1-methyl-ethyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(93 mg, 49%). ESI-MS m/z calc. 508.14, found 509.2 (M+1)+; retentiontime (Method B): 1.59 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.07 (s, 1H), 8.74 (d, J=1.1 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.34(d, J=2.2 Hz, 1H), 8.11 (d, J=2.8 Hz, 1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H),7.66 (d, J=2.9 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H),7.10 (ddt, J=7.6, 2.8, 1.4 Hz, 1H), 6.66 (d, J=1.4 Hz, 1H), 3.78 (s,3H), 1.61 (d, J=22.4 Hz, 6H) ppm. ¹⁹F NMR (376 MHz, DMSO-d6) δ −56.87,−142.08 (p, J=22.5 Hz) ppm.

Example 914-[[2-[2-(Trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(175)

Step 1:4-[[2-Fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To 2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (1.20 g, 4.08 mmol)and DIEA (1.8 mL, 10 mmol) in 1-methyl-pyrrolidin-2-one (12 mL) at 0° C.was added a solution of 4-aminopyridine-2-carboxamide (560 mg, 4.08mmol) in dichloromethane (6 mL) dropwise. The reaction was stirred atroom temperature for 16 hours. The reaction mixture was diluted withethyl acetate and washed with water. Organic layer was concentrated todryness. Silica gel chromatography (1-5% methanol/dichloromethane)provided4-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(400 mg, 11%). ESI-MS m/z calc. 395.05, found 396.6 (M+1)+; retentiontime (Method A): 0.55 minutes (1 minute run).

Step 2:4-[[2-[2-(Trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(175)

A mixture of4-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(57 mg, 0.10 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol(20 mg, 0.10 mmol), K₂CO₃ (40 mg, 0.29 mmol) in DMF (380 μL) was heatedat 100° C. The reaction mixture was filtered and diluted with DMSO (1mL). HPLC purification (1-99% acetonitrile/5 mM HCl) provided4-[[2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(42 mg, 75%) as a white solid. ESI-MS m/z calc. 586.10, found 587.2(M+1)+; retention time (method B): 1.84 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.60-8.52 (m, 1H), 8.29 (dd, J=2.2,0.6 Hz, 1H), 8.12 (d, J=2.7 Hz, 1H), 7.99-7.92 (m, 1H), 7.79 (dd, J=5.5,2.2 Hz, 1H), 7.66 (d, J=2.8 Hz, 1H), 7.35-7.27 (m, 2H), 7.23 (dd, J=2.8,0.7 Hz, 1H), 7.09-6.99 (m, 1H) ppm. ¹⁹F NMR (376 MHz, DMSO-d6) δ −56.87,−58.50, −61.65 ppm.

Example 925-[[2-[2-(Trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(176)

Step 1:5-[[2-Fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

This compound was made in an analogous fashion to Example 91, Step 1,except employing 5-aminopyridine-2-carboxamide in the amide formationstep. The yield of the desired product after purification was 560 mg(49%). ESI-MS m/z calc. 395.05, found 396.2 (M+1)+; retention time(Method B): 0.55 minutes (3 minute run).

Step 2:5-[[2-[2-(Trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(176)

A mixture of5-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(50 mg, 0.13 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol(27 mg, 0.13 mmol) and K₂CO₃ (52 mg, 0.38 mmol) in DMF (0.5 mL) washeated at 100° C. for 16 hours. The reaction was filtered, diluted withDMSO (1 mL) and purified by HPLC (1-99% acetonitrile/5 mM HCl) to obtain5-[[2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(39 mg, 52%) as a white solid. ESI-MS m/z calc. 586.10, found 587.2(M+1)+; retention time (Method B): 1.84 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.82 (d, J=2.8 Hz, 1H), 8.25 (dd,J=8.6, 2.5 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.97(d, J=1.4 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.25 (d,J=2.8 Hz, 1H), 7.07-7.01 (m, 1H) ppm.

Example 935-[[2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(186)

Step 1:2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde

A mixture of 2-chloro-3,6-difluoro-benzaldehyde (2.0 g, 11.3 mmol),2-methoxy-4-(trifluoromethoxy)phenol (2.4 g, 11.5 mmol) and Cs₂CO₃ (4.5g, 13.8 mmol) in DMF (15 mL) was stirred for 16 hours at roomtemperature. The mixture was concentrated in vacuo and the residue waspurified by silica gel chromatography (0-50% ethyl acetate/petroleumether) to provide2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde(3.6 g, 87%) as a pale yellow oil. ESI-MS m/z calc. 364.01, found 365.0(M+1)+; retention time (Method F): 1.09 minutes (1.5 minute run).

Step 2:2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic Acid

To a suspension of2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde(3.60 g, 9.87 mmol) and sodium dihydrogen phosphate hydrate (1.40 g,11.7 mmol) in tert-BuOH (20 mL)/water (10 mL) at 0° C. was added asolution of 2-methyl-2-butene (15 mL of 2 M in THF, 30 mmol). Sodiumchlorite (1.40 g, 12.4 mmol) was then added portionwise over 30 minutes.The mixture was allowed to warm to room temperature and stirred for 16hours. The reaction mixture was acidified to pH1-2 using 2M HCl, andextracted with dichloromethane. The organic layer was separated, driedby passing through a phase separation cartridge and concentrated invacuo to afford2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(3.76 g, 100%) as a white solid. ESI-MS m/z calc. 380.01, found 379.1(M−1)−; retention time (Method F): 0.71 minutes (1.5 minute run).

Step 3:2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride

A solution of2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(100 mg, 0.263 mmol) in dichloromethane (2 mL) was cooled to 0° C. Tothe solution was added DMF (2 μL, 0.03 mmol) followed by carefuladdition of oxalyl chloride (35 μL, 0.40 mmol). The ice-bath removedafter 5 minutes and the reaction stirred at room temperature for 20minutes. The reaction was concentrated in vacuo and azeotroped withdichloromethane to afford2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride.

Step 4:5-[[2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(186)

2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride was dissolved in THF (2 mL) and cooled to 0° C. DIEA (138 μL,0.792 mmol) and 5-aminopyridine-2-carboxamide (40 mg, 0.29 mmol) wereadded and the resulting suspension was stirred at 0° C. for 30 minutesand then allowed to warmed to room temperature and stirred for 16 hours.The reaction mixture was diluted with ethyl acetate and washed withwater and brine. The organic later was separated, dried by passingthrough a phase separation cartridge and concentrated in vacuo. Silicagel chromatography (0-100% ethyl acetate/petroleum ether) provided5-[[2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(85 mg, 64%). ESI-MS m/z calc. 499.06, found 500.0 (M+1)+; 497.9 (M−1)−;retention time (Method E): 3.01 minutes (5 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 11.25 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.28 (dd, J=8.6, 2.5Hz, 1H), 8.09-7.99 (m, 2H), 7.56 (s, 1H), 7.49 (t, J=9.0 Hz, 1H),7.23-7.16 (m, 2H), 6.98 (ddd, J=8.9, 2.8, 1.3 Hz, 1H), 6.84 (dd, J=9.3,3.9 Hz, 1H), 3.77 (s, 3H) ppm.

Example 944-[[2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(171)

Step 1: Methyl4-[[2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

To a solution of2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(300 mg, 0.788 mmol) in dichloromethane (5 mL) at 0° C. was added DMF (7μL, 0.08 mmol) and oxalyl chloride (235 μL, 2.69 mmol) dropwise. Thereaction was allowed to warm to room temperature over 3 hours. Thereaction mixture was concentrated in vacuo, dissolved in dichloromethane(5 mL) and cooled to 0° C. Methyl 4-aminopyridine-2-carboxylate (159 mg,1.05 mmol) was added followed by triethylamine (422 μL, 3.03 mmol). Theresulting mixture was allowed to warm to room temperature over 16 hours.The reaction mixture was diluted with water (10 mL) and extracted withdichloromethane (2×10 mL). The combined organic layers were dried overMgSO₄, filtered and concentrated in vacuo. Silica gel chromatography(0-60% ethyl acetate/petroleum ether) provided methyl4-[[2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(204 mg, 50%). ESI-MS m/z calc. 514.06, found 515.0 (M+1)+; retentiontime (Method F): 0.97 minutes (1.5 minute run).

Step 2:4-[[2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(171)

A solution of methyl4-[[2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(204 mg, 0.3963 mmol) in ammonia (6.4 mL of 7 M in methanol, 44.80 mmol)was stirred for 16 hours at room temperature. The reaction mixture wasconcentrated in vacuo and purified by HPLC (37-100% acetonitrile/0.1%ammonium hydroxide) to provide4-[[2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(142.3 mg, 70%). ESI-MS m/z calc. 499.056, found 500.0 (M+1)+; retentiontime: 3.2 minutes (5 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 11.36 (s,1H), 8.56 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.11 (d, J=2.9 Hz,1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.74-7.55 (m, 2H), 7.39-7.12 (m, 2H),7.00 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.64 (dd, J=9.0, 1.4 Hz, 1H), 3.78(s, 3H) ppm.

Example 954-[[2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(129)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide

This compound was made in an analogous fashion to Example 94, Step 1,except employing 2-bromo-5-methyl-pyridin-4-amine in the amide formationstep. The yield of the desired product after purification was 179 mg(29%). ESI-MS m/z calc. 547.98, found 551.0 (M+1)+; retention time(Method F): 1.10 minutes (1.5 minute run).

Step 2: Methyl4-[[2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

To a solution ofN-(2-bromo-5-methyl-4-pyridyl)-2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(179 mg, 0.186 mmol) in methanol (5 mL) and triethylamine (40 mg, 0.3953mmol) in a pressure tube was added Pd(dppf)Cl₂.DCM (30 mg, 0.03674mmol). Carbon monoxide was bubbled through the vigorously stirringreaction mixture for 5 minutes. The reaction mixture was sealed andheated to 75° C. for 16 hours. The reaction mixture was cooled andpassed through a pad of Celite eluting with methanol. The filtrate wasconcentrated in vacuo and purified by silica gel chromatography (0-100%ethyl acetate/petroleum ether) to provide methyl4-[[2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(87 mg, 89%). ESI-MS m/z calc. 528.07, found 529.0 (M+1)+; retentiontime (Method F): 0.99 minutes (1.5 minute run).

Step 3:4-[[2-Chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(129)

A mixture of methyl4-[[2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(87 mg, 0.16 mmol) and ammonia (4.5 mL of 7 M in methanol, 31.5 mmol)was stirred at room temperature for 16 hours. SPM32 silica metalscavenger (150 mg) was added and the reaction was stirred for 15minutes. The mixture was filtered and the filtrate concentrated invacuo. Silica gel chromatography (0-100% ethyl acetate/petroleum ether)provided4-[[2-chloro-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(54 mg, 62%) as a white solid. ESI-MS m/z calc. 513.07, found 514.0(M+1)+; retention time (Method E): 3.21 minutes (5 minute run). ¹H NMR(500 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.61-8.34 (m, 2H), 8.16-7.97 (m,1H), 7.60 (d, J=2.9 Hz, 1H), 7.48 (t, J=9.0 Hz, 1H), 7.28-7.12 (m, 2H),6.99 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.83 (dd, J=9.2, 3.9 Hz, 1H), 3.81(s, 3H), 2.29 (s, 3H) ppm.

Example 96N-(4-Carbamoyl-3-fluoro-phenyl)-2-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(132)

Step 1:N-(4-Carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(65)

A slurry of 4-amino-2-fluoro-benzamide (122 mg, 0.790 mmol) indichloromethane (2 mL) and DIEA (272 μL, 1.56 mmol) was cooled to 0° C.A slurry of cold2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (prepared as described in Example 15, Step 2, 314 mg, 0.780mmol) in dichloromethane (2 mL) was added dropwise to the stirring aminesolution. The reaction mixture was removed from ice bath after 10 minand stirred at room temperature for 2 hours. The solvent was evaporatedunder a stream of N₂ and the residue was purified by HPLC (1-99%acetonitrile/5 mM HCl) to provideN-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(298 mg, 74%). ESI-MS m/z calc. 520.07, found 521.0 (M+1)+; retentiontime (Method A): 2.56 minutes (1 minute run); retention time (Method B):1.85 minutes (3 minute run); ¹H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H),7.88 (t, J=8.7 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.66 (dd, J=13.0, 2.0Hz, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.49 (dd, J=9.1, 1.0 Hz, 2H), 7.41(dd, J=8.5, 2.0 Hz, 1H), 7.35 (d, J=9.1 Hz, 2H), 6.92 (d, J=8.8 Hz, 1H).

Step 2:N-(4-Carbamoyl-3-fluoro-phenyl)-2-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(132)

N-(4-Carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(65 mg, 0.12 mmol) was dissolved in a solution of sodium methoxide (1 mLof 0.5 M in methanol, 0.5 mmol) and heated at 80° C. for 16 hours. Thereaction mixture was filtered and purified by HPLC (1-99% acetonitrile/5mM HCl) to provideN-(4-carbamoyl-3-fluoro-phenyl)-2-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(14.6 mg, 22%). ESI-MS m/z calc. 532.09, found 533.0 (M+1)+; retentiontime (Method C): 2.59 minutes (5 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.13 (s, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.73-7.65 (m, 2H), 7.54 (d,J=16.9 Hz, 2H), 7.48-7.44 (m, 2H), 7.42 (dd, J=8.6, 2.0 Hz, 1H),7.32-7.26 (m, 2H), 6.79 (d, J=8.8 Hz, 1H), 3.92 (s, 3H) ppm.

Example 974-[[2-Methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(91)

This compound was made in an analogous fashion to Example 96, Step 2,except employing4-[[2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide48. The yield of the desired product after purification was 8 mg (14%).ESI-MS m/z calc. 515.09, found 516.0 (M+1)+; retention time (Method B):1.79 minutes (3 min run). ¹H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H),8.54 (d, J=5.5 Hz, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.11 (d, J=2.9 Hz, 1H),7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 7.67 (d, J=3.0 Hz,1H), 7.54-7.42 (m, 2H), 7.35-7.26 (m, 2H), 6.79 (d, J=8.8 Hz, 1H), 3.92(s, 3H) ppm.

Example 98N-(3-Carbamoyl-4-fluoro-phenyl)-3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(71)

Step 1: Methyl 3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoate

To a suspension of3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid (preparedas described Example 88, Step 2, in 390 mg, 1.11 mmol) indichloromethane (2.5 mL) and methanol (600 μL, 14.8 mmol) stirred underN₂ at 0° C. was added (trimethylsilyl)diazomethane (1 mL of 2 M inhexanes, 2.000 mmol) dropwise until a faint yellow color persisted. Themixture was stirred 10 minutes then several drops of acetic acid wereadded to quench excess reagent (turns colorless). The mixture wasconcentrated, dissolved in dichloromethane and washed with saturatedaqueous NaHCO₃, dried over MgSO₄, filtered and concentrated in vacuo.Silica gel chromatography (0-5% ethyl acetate/hexanes) provided methyl3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoate (400 mg, 99%).ESI-MS m/z calc. 364.01, found 365.0 (M+1)+; retention time (Method B):2.12 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 7.76 (t, J=8.8Hz, 1H), 7.45-7.39 (m, 2H), 7.22-7.14 (m, 2H), 6.96 (dd, J=9.0, 1.6 Hz,1H), 3.81 (s, 3H) ppm.

Step 2: Methyl3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoate

To a vial charged with methyl3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoate (400 mg, 1.10mmol) and bis(tri-tert-butylphosphine)palladium (0) (340 mg, 0.665 mmol)under an atmosphere of N₂ at 0° C. was added cyclopropylzinc bromide(635 mL of 0.5 M in THF, 318 mmol). The reaction mixture was warmed toroom temperature and stirred at 60° C. for 12 hours. The reaction wasdiluted with 1N HCl and extracted with dichloromethane. The organiclayer was dried over MgSO₄, filtered and concentrated in vacuo. Silicagel chromatography (0-4% ethyl acetate/hexanes) provided methyl3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoate (336 mg,83%). ESI-MS m/z calc. 370.08, found 371.2 (M+1)+; retention time(Method B): 2.2 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ7.43-7.35 (m, 2H), 7.18 (t, J=8.7 Hz, 1H), 7.13-7.06 (m, 2H), 6.83 (dd,J=8.6, 1.2 Hz, 1H), 3.76 (s, 3H), 2.03 (ddd, J=13.6, 8.6, 5.2 Hz, 1H),1.07-0.91 (m, 2H), 0.83-0.61 (m, 2H) ppm.

Step 3: 3-Cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoicAcid

To a solution of methyl3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoate (360 mg,0.972 mmol) in methanol (5 mL) and THF (5 mL) was added aqueous NaOH (5mL of 3 M, 15 mmol) followed by solid NaOH (500 mg, 12.5 mmol). Thereaction mixture was stirred at room temperature for 16 hours, thencooled to 0° C. and quenched with carefully with 6 M HCl. The suspensionwas extracted with ethyl acetate and the organic layer was dried overMgSO₄, filtered and concentrated in vacuo to obtain3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid (329mg, 95%). ESI-MS m/z calc. 356.07, found 357.1 (M+1)+; retention time(Method A): 0.76 minutes (1 minute run).

Step 4: 3-Cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoylchloride

To a solution of3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid (235mg, 0.660 mmol) and DMF (30 μL, 0.39 mmol) in dichloromethane (2 mL) at0° C. was added oxalyl chloride (100 μL, 1.15 mmol) dropwise. Themixture was stirred at room temperature for 30 minutes. Conversion wasmonitored by UPLC via test for morpholine adduct formation. The solventwas evaporated in vacuo to provide3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl chloride.

Step 5:N-(3-carbamoyl-4-fluoro-phenyl)-3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(71)

A solution of 5-amino-2-fluoro-benzamide (50 mg, 0.32 mmol) and DIEA(200 μL, 1.15 mmol) in THF (2 mL) was cooled to 0° C. and treated with asuspension of3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl chloride(120 mg, 0.3202 mmol) in THF (1 mL)/dichloromethane (1 mL). The reactionmixture was warmed to room temperature and stirred for 16 hours. Thereaction was diluted with water and extracted with dichloromethane. Theorganic layer was washed with 1 M HCl, dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-60% ethylacetate/hexanes) providedN-(3-carbamoyl-4-fluoro-phenyl)-3-cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(24 mg, 14%). ESI-MS m/z calc. 492.11, found 493.1 (M+1)+; retentiontime (Method B): 1.83 minutes (3 minute run). ¹H NMR (500 MHz, DMSO-d6)δ 10.83 (s, 1H), 7.94 (dd, J=6.6, 2.8 Hz, 1H), 7.74-7.62 (m, 3H), 7.36(d, J=8.5 Hz, 2H), 7.23 (t, J=9.5 Hz, 1H), 7.15-7.05 (m, 3H), 6.76 (d,J=8.7 Hz, 1H), 2.05 (tt, J=8.9, 5.2 Hz, 1H), 1.08-0.92 (m, 2H), 0.72 (p,J=4.9, 4.4 Hz, 2H) ppm.

Example 994-[[3-Cyclopropyl-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(72)

This compound was made in an analogous fashion to Example 98, exceptemploying 4-aminopyridine-2-carboxamide in the amide formation step(Step 5). The yield of the desired product after purification was 7 mg(4%). ESI-MS m/z calc. 475.12, found 476.2 (M+1)+; retention time(Method B): 1.79 minutes (3 minute run). ¹H NMR (500 MHz, DMSO-d6) δ11.27 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.2 Hz, 1H), 8.08 (d,J=2.8 Hz, 1H), 7.76 (dd, J=5.6, 2.2 Hz, 1H), 7.64 (d, J=2.9 Hz, 1H),7.35 (d, J=8.6 Hz, 2H), 7.20-7.02 (m, 3H), 6.78 (d, J=8.7 Hz, 1H), 2.06(tt, J=8.7, 5.1 Hz, 1H), 1.00 (h, J=4.4 Hz, 2H), 0.78-0.61 (m, 2H) ppm.

Example 100N-(3-Carbamoyl-4-fluoro-phenyl)-6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(43)

Step 1: Methyl6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

A two neck round bottom flask equipped with addition funnel was chargedwith methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(prepared as described in Example 65, Step 1, 10.0 g, 23.7 mmol) andbis(tri-t-butylphosphine)palladium (0) (1.98 g, 3.87 mmol), sealed witha septum and placed under a N₂ atmosphere, and THF (24 mL) was added,resulting in a slurry. The reaction mixture was cooled to 0° C. and theaddition funnel was charged with cyclopropylzinc bromide (57 mL of 0.5 Min THF, 28.5 mmol) as a solution in THF, which was then added dropwiseto the reaction mixture over 30 minutes. The reaction was stirred for anadditional 30 minutes, then diluted with saturated aqueous NH₄Clsolution and extracted with ethyl acetate. The layers were separated andthe organic layer was dried over Na₂SO₄, filtered and concentrated invacuo. Silica gel chromatography (0-10% ethyl acetate/hexanes) providedmethyl6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(7.3 g, 80%) and an off white solid after drying under high vacuum.ESI-MS m/z calc. 383.10, found 384.1 (M+1)+; retention time (Method A):0.63 minutes (1 minute). ¹H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.30(d, J=8.7 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.02 (ddd, J=8.9, 2.7, 1.3Hz, 1H), 6.54 (s, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 2.01 (tt, J=7.9, 4.9Hz, 1H), 0.91 (tt, J=8.0, 2.9 Hz, 4H) ppm.

Step 2:6-Cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicAcid

Methyl6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(7.30 g, 19.0 mmol) was dissolved in methanol (110 mL) and treated witha solution of NaOH (11.4 g, 285 mmol) in water (37 mL). The reactionmixture was stirred at room temperature for 1 hour. The solvents wereremoved in vacuo and the resulting slurry was dissolved in water (100mL). The solution was cooled to 0° C. and treated dropwise with aqueous6 M HCl until pH2. The resulting precipitate was collected by vacuumfiltration. The filter cake was washed with water and dried under vacuumfor 16 hours to provide6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (7.0 g, 100%) as a white powder. ESI-MS m/z calc. 369.08, found370.1 (M+1)+; retention time (Method A): 0.51 minutes (1 minute run). ¹HNMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.28 (d,J=2.8 Hz, 1H), 7.04 (ddq, J=8.7, 2.3, 1.2 Hz, 1H), 6.55 (s, 1H), 3.80(s, 3H), 2.06 (p, J=6.4 Hz, 1H), 0.95 (d, J=6.4 Hz, 4H) ppm.

Step 3:6-Cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carbonylchloride

To a solution of6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (2.1 g, 5.7 mmol) and DMF (400 μL, 5.17 mmol) in dichloromethane(20 mL) at 0° C. was added oxalyl chloride (500 μL, 5.73 mmol) dropwise.The mixture was stirred at room temperature for 30 minutes. Conversionwas monitored by UPLC via test for morpholine adduct formation. Thereaction was concentrated in vacuo to provide6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carbonylchloride.

Step 4:N-(3-Carbamoyl-4-fluoro-phenyl)-6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(43)

To a solution of 5-amino-2-fluoro-benzamide (0.88 g, 5.7 mmol) and DIEA(3.0 mL, 17 mmol) in THF (20 mL) and dichloromethane (10 mL) at 0° C.was added a solution of6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carbonylchloride (2.1 g, 5.4 mmol) in dichloromethane. The reaction mixture wasremoved from the ice bath and stirred at room temperature for 1 hour.The reaction mixture was diluted with water and extracted withdichloromethane. The organic layer was concentrated in vacuo and theresulting solid was purified using silica gel chromatography (0-60%ethyl acetate/hexanes) to provideN-(3-carbamoyl-4-fluoro-phenyl)-6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(1.1 g, 40%). ESI-MS m/z calc. 505.13, found 506.2 (M+1)+; retentiontime (Method B): 1.4 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ10.41 (s, 1H), 8.55 (s, 1H), 7.99 (dd, J=6.5, 2.8 Hz, 1H), 7.87-7.76 (m,1H), 7.69 (d, J=14.5 Hz, 2H), 7.45 (d, J=8.8 Hz, 1H), 7.32-7.18 (m, 2H),7.07 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.59 (s, 1H), 3.80 (s, 3H), 2.07 (p,J=6.7 Hz, 1H), 0.99-0.87 (m, 4H) ppm.

Example 101N-(2-Carbamoyl-4-pyridyl)-6-cyclopropyl-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(372)

This compound was made in an analogous fashion to Example 100 exceptemploying 4-aminopyridine-2-carboxamide in the amide formation step(Step 4). The yield of the desired product after purification was 296 mg(21%). ESI-MS m/z calc. 488.13, found 489.2 (M+1)+; retention time(Method B): 1.39 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ10.84 (s, 1H), 8.58 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.1 Hz,1H), 8.09 (d, J=2.9 Hz, 1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d,J=2.9 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.7 Hz, 1H), 7.07(ddt, J=8.7, 2.4, 1.2 Hz, 1H), 6.62 (s, 1H), 3.79 (s, 3H), 2.13-2.01 (m,1H), 0.97-0.91 (m, 4H) ppm.

Example 102N-(2-Carbamoyl-4-pyridyl)-6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(107)

Step 1: Methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-vinyl-pyridine-3-carboxylate

Methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(3.0 g, 7.1 mmol) was dissolved in acetonitrile (30 mL) and degassedwith N₂ for 10 minutes. To the solution was added vinylboronic acidpinacol ester (2.8 g, 18 mmol), aqueous K₂CO₃ (10.7 mL of 2 M, 21.3mmol) and Pd(dppf)Cl₂.DCM (0.260 g, 0.355 mmol). The reaction was heatedunder N₂ atmosphere at 80° C. for 40 minutes. The reaction was dilutedwith ethyl acetate (100 mL) and washed with aqueous NaHCO₃ solution,water, 10% citric acid and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. Silica gel chromatography(0-40% ethyl acetate/hexanes) provided4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-vinyl-pyridine-3-carboxylate(2.8 g, 85%). ESI-MS m/z calc. 369.08, found 370.3 (M+1)+; retentiontime (Method B): 1.5 minutes (3 minute run). ¹H NMR (400 MHz, DMF-d7) δ8.90 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.30 (d, J=2.7 Hz, 1H), 6.88-6.71(m, 1H), 6.68 (s, 1H), 6.31 (dd, J=17.3, 1.7 Hz, 1H), 5.55 (dd, J=10.6,1.7 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H) ppm.

Step 2: Methyl6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

A solution of methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-vinyl-pyridine-3-carboxylate(235 mg, 0.636 mmol) in THF (2.4 mL) was treated with sodium iodide (48mg, 0.32 mmol) and trimethyl(trifluoromethyl)silane (362 mg, 2.55 mmol)and heated at 65° C. Additional sodium iodide (24 mg, 0.16 mmol) andtrimethyl(trifluoromethyl)silane (362 mg, 2.55 mmol) were added after 1hour, and the reaction again charged withtrimethyl(trifluoromethyl)silane (362 mg, 2.55 mmol) added after 2hours. The reaction was stirred for 1 additional hour, then cooled andpartitioned between ethyl acetate and water. The layers were separatedand the aqueous layer was extracted with additional ethyl acetate. Thecombined organic layers were washed with brine, dried over MgSO₄ andconcentrated in vacuo. Silica gel chromatography (0-100% ethylacetate/hexanes) provided6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(82 mg, 28%) as a yellow solid. ESI-MS m/z calc. 419.08, found 420.2(M+1)+; retention time (Method A): 0.74 minutes (1 minute run).

Step 3:6-(2,2-Difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicAcid

To a solution of methyl6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(82 mg, 0.18 mmol) in methanol (738 μL) was added sodium hydroxide (574μL of 3 M, 1.72 mmol), followed by THF (1 mL). The reaction mixture wasstirred at room temperature for 2 hours, then cooled to 0° C. andquenched dropwise with 6N HCl. The mixture was extracted with ethylacetate and the organic layer was dried over MgSO₄, filtered andconcentrated in vacuo to obtain6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (60 mg, 84%). ESI-MS m/z calc. 405.06, found 406.1 (M+1)+;retention time (Method A): 0.52 minutes (1 minute run).

Step 4:N-(2-Carbamoyl-4-pyridyl)-6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(107)

A vial was charged with6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (55 mg, 0.14 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(49 mg, 0.15 mmol), iron (III) acetylacetonate (3 mg, 0.008 mmol) in2-propanol (550 μL) and heated at 83° C. under air atmosphere for 20hours. The reaction mixture was concentrated in vacuo and purified usingsilica gel chromatography (0-60% ethyl acetate/hexanes) to obtainN-(2-carbamoyl-4-pyridyl)-6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(4 mg, 5%). ESI-MS m/z calc. 524.11, found 525.1 (M+1)+; retention time(Method B): 1.54 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.01 (s, 1H), 8.68 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.2 Hz,1H), 8.11 (d, J=2.9 Hz, 1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (d,J=2.9 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 7.08(ddd, J=8.9, 2.8, 1.3 Hz, 1H), 6.82 (s, 1H), 3.79 (s, 3H), 3.31-3.22 (m,1H), 2.30 (dq, J=13.4, 7.3, 6.7 Hz, 1H), 2.08-1.87 (m, 1H) ppm. ¹⁹F NMR(376 MHz, DMSO-d6) δ −56.80, −122.59, −122.99, −141.98, −142.36 ppm.

Example 103N-(3-Carbamoyl-4-fluoro-phenyl)-6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(108)

A solution of 5-amino-2-fluoro-benzamide (7.0 mg, 0.04 mmol),6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (15 mg, 0.04 mmol) and HATU (15 mg, 0.04 mmol) in DMF (225 μL) wastreated with triethylamine (16 μL, 0.11 mmol) and stirred at roomtemperature for 2 hours. The reaction mixture was diluted with DMSO (1mL) and purified by HPLC (1-99% acetonitrile/5 mM HCl) to obtainN-(3-carbamoyl-4-fluoro-phenyl)-6-(2,2-difluorocyclopropyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(5 mg, 24%). ESI-MS m/z calc. 541.11, found 542.1 (M+1)+; retention time(Method B): 1.56 minutes (3 minute run).

Example 104N-(3-Carbamoyl-4-fluoro-phenyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(32)

Step 1:3-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicAcid

To 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (1.40 g, 6.70mmol) in DMF (14 mL) was added 2-methoxy-4-(trifluoromethoxy)phenol(1.39 g, 6.69 mmol) and Cs₂CO₃ (6.54 g, 20.1 mmol). The reaction wasstirred at 90° C. for 72 hours. The reaction was filtered through a padof Celite and the filtrate was partitioned between water and ethylacetate. The organic layer was washed with water, aqueous NaHCO₃ andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Silica gelchromatography (10-100% ethyl acetate/hexanes) provided3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid (1.80 g, 68%) as a white solid. ESI-MS m/z calc. 397.04, found398.2 (M+1)+; retention time (Method A): 0.61 minutes (1 minute run).

Step 2:3-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonylchloride

To a solution of3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid (600 mg, 1.51 mmol) and DMF (12 μL, 0.15 mmol) in dichloromethane(9 mL) at 0° C. was added oxalyl chloride (0.50 mL, 5.7 mmol) dropwise.The mixture was heated to 50° C. for 10 minutes. Conversion wasmonitored by UPLC via test for the morpholine adduct. The reactionmixture was concentrated, then evaporated with dichloromethane (3×50 mL)to provide3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonylchloride (625 mg, 100%).

Step 3:N-(3-Carbamoyl-4-fluoro-phenyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(32)

5-amino-2-fluoro-benzamide (19 mg, 0.12 mmol) was dissolved indichloromethane (1 mL) and DIEA (63 μL, 0.36 mmol) and treated with asolution of3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonylchloride (50 mg, 0.12 mmol) in dichloromethane (1 mL). The reaction wasstirred for 30 minutes then concentrated in vacuo. The residue wasdissolved in DMSO (1 mL) and treated with water to afford a precipitate.The precipitate was filtered, then triturated and filtered sequentiallywith acetonitrile and diethyl ether. The resulting solid was dried undervacuum to provideN-(3-carbamoyl-4-fluoro-phenyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(22 mg, 34%). ESI-MS m/z calc. 533.08, found 534.2 (M+1)+; retentiontime (Method B): 1.71 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.90 (s, 1H), 8.82 (dd, J=1.9, 0.9 Hz, 1H), 8.05 (dd, J=6.5, 2.8 Hz,1H), 7.81 (ddd, J=8.9, 4.5, 2.8 Hz, 1H), 7.72 (s, 1H), 7.68 (s, 1H),7.62 (d, J=1.8 Hz, 1H), 7.28 (dt, J=8.9, 5.1 Hz, 2H), 7.23 (d, J=2.7 Hz,1H), 7.01 (ddd, J=8.9, 2.7, 1.3 Hz, 1H), 3.78 (s, 3H) ppm.

Example 105N-(3-Carbamoylphenyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(31)

This compound was made in an analogous fashion to Example 104 exceptemploying 3-aminobenzamide in the amide formation step (Step 3). Theyield of the desired product after purification was 18 mg (29%). ESI-MSm/z calc. 515.09, found 516.2 (M+1)+; retention time (Method B): 0.67minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.82(dd, J=1.8, 0.9 Hz, 1H), 8.21 (t, J=1.9 Hz, 1H), 7.97 (s, 1H), 7.83(ddd, J=8.0, 2.2, 1.0 Hz, 1H), 7.64-7.59 (m, 2H), 7.43 (t, J=7.9 Hz,1H), 7.38 (s, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.01(ddd, J=8.8, 2.7, 1.3 Hz, 1H), 3.78 (s, 3H) ppm.

Example 106N-(3-Carbamoyl-4-fluoro-phenyl)-2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxamide(122)

Step 1: Methyl 6-chloro-2,2-difluoro-1,3-benzodioxole-5-carboxylate

Sulfuric acid (693 μL, 13.0 mmol) was added to a solution of6-chloro-2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (2.05 g, 8.67mmol) in methanol (50 mL) and the resulting mixture was heated at 65° C.for 18 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was taken up in ethyl acetate andwater and the layers were separated. The organic layer was washed with asaturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered andconcentrated to provide methyl6-chloro-2,2-difluoro-1,3-benzodioxole-5-carboxylate (1.96 g, 90%) as abrown solid. ESI-MS m/z calc. 249.98, found 250.9 (M+1)+; retention time(Method A): 0.64 minutes (1 minute run). ¹H NMR (400 MHz, DMSO-d6) δ7.89 (s, 1H), 7.83 (s, 1H), 3.86 (s, 3H) ppm.

Step 2: Methyl2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylate

A mixture of methyl 6-chloro-2,2-difluoro-1,3-benzodioxole-5-carboxylate(3.0 g, 12 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (5.0 g, 24 mmol),K₂CO₃ (3.4 g, 24 mmol), Cu (950 mg, 15.0 mmol), and copper iodide (364mg, 1.91 mmol) in nitrobenzene (41 mL) was stirred at 170° C. for 25minutes. The reaction was cooled to room temperature and filteredthrough a pad of Celite and rinsed with ethyl acetate. The filtrate wasevaporated in vacuo and purified using silica gel chromatography (0-15%ethyl acetate/hexanes) to provide methyl2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylate(540 mg, 11%) as a yellow solid. ESI-MS m/z calc. 422.04, found 423.0(M+1)+; retention time (Method C): 2.97 minutes (5 minute run).

Step 3:2,2-Difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicAcid

A solution of methyl2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylate(140 mg, 0.332 mmol) in methanol (3 mL) was treated with aqueous NaOH(1.5 mL of 1 M, 1.5 mmol). The reaction mixture was stirred at 60° C.for 75 minutes. The reaction was cooled and acidified to pH1 with 12 MHCl. The mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to provide2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicacid (135 mg, 100%) as a light yellow solid. ESI-MS m/z calc. 408.03,found 409.0 (M+1)+; retention time (Method B): 0.71 minutes (3 minuterun).

Step 4:N-(3-Carbamoyl-4-fluoro-phenyl)-2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxamide(122)

2,2-Difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicacid (30 mg, 0.07 mmol) and HATU (34 mg, 0.09 mmol) were combined in DMF(500 μL) and DIEA (27 μL, 0.16 mmol), and stirred for 5 minutes.5-Amino-2-fluoro-benzamide (12 mg, 0.08 mmol) was added in one portionand the reaction was stirred for 1 hour. HPLC purification (10-99%acetonitrile/5 mM HCl) providedN-(3-carbamoyl-4-fluoro-phenyl)-2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxamide(19 mg, 48%) as a white solid. ESI-MS m/z calc. 544.07, found 544.8(M+1)+; retention time (Method C): 2.7 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.95 (dd, J=6.4, 2.8 Hz, 1H),7.80-7.60 (m, 4H), 7.24 (dd, J=10.2, 9.0 Hz, 1H), 7.18-7.10 (m, 3H),7.00-6.80 (m, 1H), 3.77 (s, 3H) ppm.

Example 1075-[[2,2-Difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(197)

This compound was made in an analogous fashion to Example 106 exceptemploying 5-aminopyridine-2-carboxamide in the amide formation step(Step 4). The yield of the desired product after purification was 18 mg(21%). ESI-MS m/z calc. 527.08, found 527.9 (M+1)+; retention time(Method C): 2.64 minutes (5 minute run). ¹H-NMR (400 MHz, DMSO-d6) δ10.82 (s, 1H), 8.84 (d, J=2.4 Hz, 1H), 8.21 (dd, J=8.5, 2.5 Hz, 1H),8.02 (d, J=8.7 Hz, 2H), 7.82 (s, 1H), 7.56 (s, 1H), 7.20-7.12 (m, 3H),6.94 (ddd, J=8.9, 2.8, 1.3 Hz, 1H), 3.74 (s, 3H) ppm.

Example 1084-[[2,2-Difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(121)

A vial charged with2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicacid (27 mg, 0.066 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Preparation 1, 25 mg, 0.075 mmol) andtris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (2 mg, 0.006 mmol) in2-propanol (0.4 mL) was heated at 80° C. under an atmosphere of air for20 hours. The reaction mixture was cooled to room temperature anddiluted with ethyl acetate and 1 M HCl. The two layers were separatedand the aqueous layer was extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. Silica gel chromatography (0-30% ethyl acetate/dichloromethane)provided4-[[2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(18.5 mg, 53%) as a white solid. ESI-MS m/z calc. 527.08, found 528.0(M+1)+; retention time (Method C): 2.62 minutes (5 minutes run). ¹H NMR(400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.27 (d,J=2.2 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.84-7.79 (m, 2H), 7.62 (d, J=3.0Hz, 1H), 7.18-7.14 (m, 2H), 7.13 (d, J=2.9 Hz, 1H), 7.03-6.66 (m, 1H),3.75 (s, 3H) ppm.

Example 1094-[[5-(1,1,2,2,2-pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(80)

Step 1: 2-Fluoro-5-(1,1,2,2,2-pentafluoroethyl)benzoic Acid

Activation of copper reagent: 20 g of bronze copper powder was stirredin −250 mL of a solution of 4 g iodine in acetone for 15 minutes untilthe iodine solution was decolorized (purple turning to colorless). Theproduct was collected in a filter funnel and added to a solution of 12 MHCl in acetone (1:1, v/v, 80 mL). After stirring for 5 minutes the solidwas filtered, washed with acetone (8×40 mL) and air dried for 30minutes. The activation was carried out directly prior to reaction.

5-Bromo-2-fluoro-benzoic acid (5.0 g, 22.8 mmol) was dissolved in DMSO(100 mL) under N₂ atmosphere and cooled to 0° C. The1,1,1,2,2-pentafluoro-2-iodo-ethane canister was cooled to 0° C. andthen 1,1,1,2,2-pentafluoro-2-iodo-ethane (39.3 g, 160 mmol) was pouredinto reaction flask under N₂ followed by the activated copper reagent(12.3 g, 193 mmol). The flask was sealed under N₂ and heated for 30minutes at 100° C. and then the temperature was raised to 120° C. andstirred for 48 hours. The reaction was cooled to room temperature,filtered and the filter cake was rinsed with DMSO (60 mL). The filtratewas diluted with ethyl acetate (450 mL) and filtered through a pad ofCelite. To the filtrate was added 1 N HCl and the layers separated. Theaqueous layer was extracted with additional ethyl acetate, and thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-30% ethylacetate/dichloromethane) provided2-fluoro-5-(1,1,2,2,2-pentafluoroethyl)benzoic acid (2.0606 g, 35%) as alight brown solid. ESI-MS m/z calc. 258.01, found 259.2 (M+1)+;retention time (Method B): 1.36 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 13.84 (s, 1H), 8.11 (dd, J=6.6, 2.7 Hz, 1H), 8.07-7.96 (m,1H), 7.81-7.41 (m, 1H) ppm.

Step 2:5-(1,1,2,2,2-Pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoicAcid

2-Fluoro-5-(1,1,2,2,2-pentafluoroethyl)benzoic acid (500 mg, 1.94 mmol),Cs₂CO₃ (1.36 g, 4.17 mmol), 4-(trifluoromethoxy)phenol (459 mg, 2.58mmol) and DMF (10 mL) were combined in a sealed vial and heated at 150°C. for 14 hours. The reaction was cooled, diluted with 1 N HCl andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Silicagel chromatography (0-15% ethyl acetate/dichloromethane) provided5-(1,1,2,2,2-pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoicacid (116 mg, 14%) as a brown solid. ESI-MS m/z calc. 416.03, found417.1 (M+1)+; retention time (Method B): 1.92 minutes (3 minute run).

Step 3:5-(1,1,2,2,2-Pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoylchloride

To a solution of5-(1,1,2,2,2-pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoicacid (114 mg, 0.274 mmol) and DMF (10 μL, 0.13 mmol) in dichloromethane(1.5 mL) at 0° C. was added oxalyl chloride (150 μL, 1.72 mmol)dropwise. The reaction was then allowed to warn to room temperature.Conversion was monitored via test for piperidine adduct formation. After35 minutes the reaction mixture was concentrated to provide5-(1,1,2,2,2-pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoylchloride.

Step 4:4-[[5-(1,1,2,2,2-Pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(80)

To a solution of 4-aminopyridine-2-carboxamide (19 mg, 0.14 mmol) in THF(1 mL) and DIEA (72 μL, 0.41 mmol) at 0° C. was added a slurry of5-(1,1,2,2,2-pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoylchloride (60 mg, 0.14 mmol) in THF (1 mL) dropwise. The reaction wasallowed to come to room temperature and stirred for 4 hours. The solventwas evaporated under a stream of N₂. HPLC purification (1-99%acetonitrile/5 mM HCl) provided4-[[5-(1,1,2,2,2-pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(10 mg, 13%). ESI-MS m/z calc. 535.08, found 535.9 (M+1)+; retentiontime (Method B): 1.95 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.12 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.10(d, J=2.8 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.96-7.76 (m, 2H), 7.65 (d,J=2.8 Hz, 1H), 7.56-7.39 (m, 2H), 7.39-7.24 (m, 2H), 7.14 (d, J=8.8 Hz,1H) ppm.

Example 110N-(3-Carbamoyl-4-fluoro-phenyl)-5-(1,1,2,2,2-pentafluoroethyl)-2-[4-(trifluoromethoxy)phenoxy]benzamide(79)

This compound was made in an analogous fashion to Example 109 exceptemploying 5-amino-2-fluoro-benzamide in the amide formation step (Step4). The yield of the desired product after purification was 28 mg (36%).ESI-MS m/z calc. 552.07, found 553.0 (M+1)+; retention time (Method B):2.0 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H),8.07-7.91 (m, 2H), 7.87-7.75 (m, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.54-7.40(m, 2H), 7.37-7.31 (m, 2H), 7.27 (dd, J=10.1, 8.9 Hz, 1H), 7.12 (d,J=8.7 Hz, 1H) ppm.

Example 1115-[[2,4-Dichloro-6-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxamide(182)

Step 1: 2,4-Dichloro-6-fluoro-benzoic Acid

To a solution of 2,4-dichloro-6-fluoro-benzaldehyde (1.0 g, 5.2 mmol),2-methyl-2-butene (1.8 g, 2.7 mL, 26 mmol) and sodium dihydrogenphosphate hydrate (2.1 g, 16 mmol) in tert-BuOH (5.0 mL)/acetonitrile(3.25 mL)/water (5.0 mL) at 0° C. was added sodium chlorite (1.4 g, 16mmol) and the reaction mixture was stirred for 1 hour. The cold reactionmixture was then acidified with 1 M HCl (50 mL) and extracted with ethylacetate (3×). The combined organics were washed with 1 M HCl and brine,dried over Na₂SO₄, filtered and evaporated to dryness. The residue wastriturated in 20% diethyl ether/hexanes and filtered to provide2,4-dichloro-6-fluoro-benzoic acid (700 mg, 65%) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 14.29 (br s, 1H), 7.70-7.63 (m, 2H) ppm.

Step 2: 2,4-Dichloro-6-fluoro-benzoyl chloride

To a solution of 2,4-dichloro-6-fluoro-benzoic acid (5.1 g, 24 mmol) andDMF (173 μL, 2.23 mmol) in dichloromethane (50 mL) at 0° C. was addedoxalyl chloride (10.2 mL, 117 mmol) dropwise. The mixture was stirred atroom temperature for 5 hours under N₂ atmosphere. Conversion wasmonitored by UPLC via test for morpholine adduct formation. The solventwas evaporated under reduced pressure to afford2,4-dichloro-6-fluoro-benzoyl chloride.

Step 3: 5-[(2,4-Dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide

To 2,4-dichloro-6-fluoro-benzoyl chloride (2.5 g, 11 mmol) and DIEA (4.8mL, 27.5 mmol) in NMP (25 mL) at 0° C. was added a solution of5-aminopyridine-2-carboxamide (1.5 g, 11 mmol) in dichloromethane (12.5mL) dropwise. The reaction was stirred at room temperature for 16 hours.Water (20 mL) was added to the reaction mixture and the resulting solidwas filtered to provide5-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (1.2 g,33%). ESI-MS m/z calc. 327.00, found 328.1 (M+1)+; retention time(Method B): 1.16 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.34 (s, 1H), 8.88-8.82 (m, 1H), 8.29 (dd, J=8.5, 2.5 Hz, 1H),8.12-8.01 (m, 2H), 7.76 (dq, J=4.2, 2.0 Hz, 2H), 7.58 (s, 1H) ppm.

Step 4:5-[[2,4-Dichloro-6-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxamide(182)

To 5-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (44mg, 0.13 mmol) in DMF (1 mL) was added 4-fluoro-2-methoxy-phenol (19 mg,15 μL, 0.13 mmol) followed by K₂CO₃ (56 mg, 0.40 mmol). The reaction washeated at 80° C. for 1 hour. The reaction was diluted with DMSO andpurified by HPLC (1-99% acetonitrile/5 mM HCl) to provide5-[[2,4-dichloro-6-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxamide(39 mg, 63%). ESI-MS m/z calc. 449.03, found 449.95 (M+1)+; retentiontime (Method B): 1.66 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.23 (s, 1H), 8.88 (d, J=2.6 Hz, 1H), 8.31 (dd, J=8.6, 2.5 Hz, 1H),8.06 (d, J=8.7 Hz, 1H), 8.04 (s, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.51 (d,J=1.8 Hz, 1H), 7.23 (dd, J=8.9, 5.9 Hz, 1H), 7.15 (dd, J=10.7, 2.9 Hz,1H), 6.85 (td, J=8.4, 2.9 Hz, 1H), 6.64 (d, J=1.8 Hz, 1H), 3.78 (s, 3H)ppm.

Example 1124-[[2,4-Dichloro-6-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxamide(178)

Step 1: 4-[(2,4-Dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide

This compound was made in an analogous fashion to Example 111, step 3,except employing 4-aminopyridine-2-carboxamide in the amide formationstep. The yield of the desired product after purification was 1.05 g(29%). ESI-MS m/z calc. 327.00, found 328.1 (M+1)+; retention time(Method B): 1.16 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.42 (s, 1H), 8.58 (d, J=5.4 Hz, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.12 (d,J=2.8 Hz, 1H), 7.88-7.51 (m, 4H) ppm.

Step 2:4-[[2,4-Dichloro-6-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxamide(178)

To 4-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (45mg, 0.14 mmol) in DMF was added 4-fluoro-2-methoxy-phenol (20 mg, 16 μL,0.14 mmol) followed by K₂CO₃ (57 mg, 0.41 mmol). The reaction was heatedat 80° C. for 30 minutes, then diluted with DMSO (0.5 mL), filtered, andpurified by HPLC (1-99% acetonitrile/5 mM HCl) to provide4-[[2,4-dichloro-6-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]pyridine-2-carboxamide(34 mg, 54%). ESI-MS m/z calc. 449.03, found 449.95 (M+1)+; retentiontime (Method B): 1.65 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.34 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.13(d, J=2.7 Hz, 1H), 7.85 (dd, J=5.5, 2.2 Hz, 1H), 7.68 (s, 1H), 7.50 (d,J=1.8 Hz, 1H), 7.22 (dd, J=8.9, 5.8 Hz, 1H), 7.14 (dd, J=10.7, 2.9 Hz,1H), 6.84 (ddd, J=8.9, 8.1, 2.9 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H), 3.77(s, 3H) ppm.

Example 113N-(3-Carbamoylphenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(28)

Step 1:2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzaldehyde

To a solution of 2-fluoro-4-(trifluoromethyl)benzaldehyde (923 mg, 655μL, 4.81 mmol) in DMF (5 mL) was added2-methoxy-4-(trifluoromethoxy)phenol (1000 mg, 655 μL, 4.81 mmol) andCs₂CO₃ (1.57 g, 4.81 mmol). The mixture was heated at 100° C. for 2hours. The reaction mixture was diluted with water and extracted withethyl acetate (3×). The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo. Silica gel chromatography (1-50%ethyl acetate/hexanes) provided2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzaldehyde(1.83 g, 91%). ESI-MS m/z calc. 380.05, found 381.1 (M+1)+; retentiontime (Method A): 0.77 minutes (1 minute run).

Step 2:2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicAcid

To a solution of2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzaldehyde(1.83 g, 4.81 mmol) in tert-BuOH (18 mL), water (12 mL) and acetonitrile(12 mL) was added sodium dihydrogen phosphate hydrate (577 mg, 4.81mmol) and 2-methyl-2-butene (1.5 g, 2.3 mL, 22 mmol). Sodium chlorite(522 mg, 5.78 mmol) was then added portionwise and the reaction mixturewas stirred for 1 hour at room temperature. The reaction was adjusted topH2 by the addition of 1 M HCl solution and the reaction mixture wasextracted with ethyl acetate (3×). The combined organic layers weredried over MgSO₄, filtered, and concentrated in vacuo to provide2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (1.65 g, 87%) as an off-white solid. ESI-MS m/z calc. 396.04, found397.1 (M+1)+; retention time (Method B): 1.81 minutes (3 minute run). ¹HNMR (400 MHz, DMSO-d6) δ 13.43 (s, 1H), 7.99 (dd, J=8.1, 0.9 Hz, 1H),7.59-7.52 (m, 1H), 7.24 (d, J=2.8 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 6.99(qd, J=3.7, 3.2, 1.3 Hz, 2H), 3.80 (s, 3H) ppm.

Step 3:N-(3-Carbamoylphenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(28)

To a solution of2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (50 mg, 0.13 mmol), 3-aminobenzamide (17 mg, 0.13 mmol) and HATU(62 mg, 0.16 mmol) in DMF (1 mL) was added DIEA (66 μL, 0.38 mmol). Thereaction was stirred at room temperature for 16 hours. HPLC purification(1-99% acetonitrile/5 mM HCl) affordedN-(3-carbamoylphenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(34 mg, 52%). ESI-MS m/z calc. 514.10, found 515.2 (M+1)+; retentiontime (Method B): 1.91 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.60 (s, 1H), 8.17 (t, J=1.9 Hz, 1H), 7.97 (s, 1H), 7.90-7.84 (m,1H), 7.82 (ddd, J=8.1, 2.3, 1.0 Hz, 1H), 7.60 (dt, J=7.9, 1.3 Hz, 2H),7.42 (t, J=7.9 Hz, 1H), 7.38 (s, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.23 (d,J=2.7 Hz, 1H), 7.04 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.98 (d, J=1.6 Hz,1H), 3.78 (s, 3H) ppm.

Example 114N-(3-Carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(27)

This compound was made in an analogous fashion to Example 113 exceptemploying 5-amino-2-fluoro-benzamide in the amide formation step (Step3). The yield of the desired product after purification was 18 mg (33%).ESI-MS m/z calc. 532.09, found 533.08 (M+1)+; retention time (Method B):1.76 minutes (3 minute run).

Example 1154-[[2,3-Difluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(64)

Step 1: 2,3-Difluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic Acid

To a pressure flask was added 6-bromo-2,3-difluoro-benzoic acid (5.0 g,21 mmol), 4-(trifluoromethoxy)phenol (3.8 g, 21 mmol), Cs₂CO₃ (7.0 g,21.5 mmol) and toluene (150 mL). The reaction mixture was bubbled withN₂ for 10 minutes, and then copper iodide (840 mg, 4.41 mmol) was added.The flask was flushed with N₂, capped, and heated at 100° C. withvigorous stirring for 22 hours. The mixture was allowed to cool and wasdiluted with ethyl acetate and water. The water layer was acidified with12 M HCl to pH1 and the product was extracted into ethyl acetate. Theorganic layer was washed with 1 M HCl and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. Silica gel chromatography (0-30%ethyl acetate/hexanes) provided2,3-difluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid (3.4 g, 48%).ESI-MS m/z calc. 334.03, found 335.1 (M+1)+; retention time (Method C):2.23 minutes (5 minute run).

Step 2: 2,3-Difluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl chloride

To a solution of 2,3-difluoro-6-[4-(trifluoromethoxy)phenoxy]benzoicacid (1.35 g, 4.04 mmol) and DMF (20 μL, 0.26 mmol) in dichloromethane(12 mL) at 0° C. was added oxalyl chloride (2.0 mL, 23 mmol) dropwise.The reaction was removed from the ice bath and was stirred under N₂atmosphere for 50 minutes. Conversion was monitored by UPLC via test forpiperidine adduct formation. The solvent was evaporated under reducedpressure to afford 2,3-difluoro-6-[4-(trifluoromethoxy)phenoxy]benzoylchloride (1.4 g, 98%).

Step 3:4-[[2,3-Difluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(64)

To a solution of 4-aminopyridine-2-carboxamide (58 mg, 0.43 mmol) andDIEA (222 μL, 1.28 mmol) in dichloromethane (1 mL) at 0° C. was added aslurry of 2,3-difluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl chloride(150 mg, 0.425 mmol) in dichloromethane (1 mL) slowly and the reactionwas stirred at room temperature for 2 hours. The solvent was evaporatedunder a stream of N₂. HPLC purification (1-99% acetonitrile/5 mM HCl)provided4-[[2,3-difluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(33 mg, 17%). ESI-MS m/z calc. 453.08, found 454.1 (M+1)+; retentiontime (Method B): 1.55 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.39 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.10(d, J=2.7 Hz, 1H), 7.76 (dd, J=5.5, 2.2 Hz, 1H), 7.70-7.59 (m, 2H),7.42-7.35 (m, 2H), 7.21-7.13 (m, 2H), 7.02-6.92 (m, 1H) ppm.

Example 116N-(3-Carbamoyl-4-fluoro-phenyl)-2,3-difluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(63)

This compound was made in an analogous fashion to Example 115 exceptemploying 5-amino-2-fluoro-benzamide in the amide formation step (Step3). The yield of the desired product after purification was 84 mg (42%).ESI-MS m/z calc. 470.07, found 471.1 (M+1)+; retention time (Method B):1.6 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H),7.92 (dd, J=6.4, 2.8 Hz, 1H), 7.74-7.65 (m, 3H), 7.65-7.55 (m, 1H),7.43-7.36 (m, 2H), 7.26 (dd, J=10.1, 9.0 Hz, 1H), 7.22-7.11 (m, 2H),7.00-6.90 (m, 1H) ppm.

Example 1174-[[5-Fluoro-2-[4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(76)

Step 1: 2,5-Difluoro-4-(trifluoromethyl)benzoyl chloride

To a solution of 2,5-difluoro-4-(trifluoromethyl)benzoic acid (2.00 g,8.85 mmol) and DMF (63 μL, 0.81 mmol) in dichloromethane (23 mL) at 0°C. was added oxalyl chloride (5.5 g, 3.8 mL, 43 mmol) dropwise. Themixture was stirred at 50° C. for 40 minutes under N₂ atmosphere and theconversion was monitored by UPLC via test for piperidine adductformation. The solvent was evaporated under reduced pressure to afford2,5-difluoro-4-(trifluoromethyl)benzoyl chloride (1.90 g, 88%).

Step 2:4-[[2,5-Difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of 4-aminopyridine-2-carboxamide (0.73 g, 5.3 mmol), DMAP(0.13 g, 1.1 mmol) and DIEA (2.1 g, 2.8 mL, 16 mmol) in dichloromethane(13 mL) at 0° C. was added a solution of2,5-difluoro-4-(trifluoromethyl)benzoyl chloride (1.3 g, 5.3 mmol) inTHF (13 mL) dropwise. The reaction was stirred at room temperature for16 hours. The reaction was diluted with ethyl acetate and washed withaqueous NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. Silica gel chromatography(0-40% ethyl acetate/hexanes) provided4-[[2,5-difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1.7 g, 85%). ESI-MS m/z calc. 345.05, found 346.2 (M+1)+; retentiontime (Method A): 0.53 minutes (1 minute run).

Step 3:4-[[5-Fluoro-2-[4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(76)

A mixture of4-[[2,5-difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(100 mg, 0.27 mmol), 4-(trifluoromethoxy)phenol (47 mg, 34 μL, 0.27mmol), K₂CO₃ (111 mg, 0.80 mmol) and DMF (1 mL) was heated at 80° C. for16 hours. HPLC purification (1-99% acetonitrile/5 mM HCl) provided4-[[5-fluoro-2-[4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(40 mg, 30%) as a white solid. ESI-MS m/z calc. 503.07, found 504.2(M+1)+; retention time (Method B): 1.77 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.26 (d,J=2.2 Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 8.02 (d, J=10.1 Hz, 1H), 7.77(dd, J=5.6, 2.2 Hz, 1H), 7.66 (d, J=2.8 Hz, 1H), 7.59 (d, J=5.8 Hz, 1H),7.40-7.32 (m, 2H), 7.21-7.09 (m, 2H) ppm. ¹⁹F NMR (376 MHz, DMSO-d6) δ−57.22, −60.39, −120.34 ppm.

Example 118N-(3-Carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(77)

Step 1:N-(3-Carbamoyl-4-fluoro-phenyl)-2,5-difluoro-4-(trifluoromethyl)benzamide

This compound was made in an analogous fashion to Example 117, Step 2,except employing 5-amino-2-fluoro-benzamide in the amide formation step.The yield of the desired product after purification was 1.0 g (89%).ESI-MS m/z calc. 362.05, found 363.2 (M+1)+; retention time (Method A):0.55 minutes (1 minute run).

Step 2:N-(3-Carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(77)

A mixture ofN-(3-carbamoyl-4-fluoro-phenyl)-2,5-difluoro-4-(trifluoromethyl)benzamide(100 mg, 0.254 mmol), 4-(trifluoromethoxy)phenol (45 mg, 0.25 mmol),K₂CO₃ (105 mg, 0.762 mmol) in DMF (1 mL) was heated at 100° C. for 2hours. The reaction mixture was filtered, diluted with DMSO and purifiedby HPLC (1-99% acetonitrile/5 mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide(19 mg, 14%) as a white solid. ESI-MS m/z calc. 520.07, found 521.1(M+1)+; retention time (Method B): 1.9 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.07-7.87 (m, 2H), 7.78-7.63 (m,3H), 7.56 (d, J=5.8 Hz, 1H), 7.44-7.32 (m, 2H), 7.32-7.24 (m, 1H),7.22-7.05 (m, 2H) ppm. ¹⁹F NMR (376 MHz, DMSO-d6) δ −57.19, −60.36,−118.49, −120.43 ppm.

Example 1193-Fluoro-6-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]pyridine-2-carboxamide(164)

Step 1: Methyl 3,5-difluoropyridine-4-carboxylate

3,5-Difluoropyridine-4-carboxylic acid (5.39 g, 33.9 mmol) was suspendedin methanol (50 mL) and stirred vigorously with heating (71° C.) asthionyl chloride (5.4 mL, 74 mmol) was added dropwise. The reaction washeated for 24 hours, and then the heat was removed and the reaction wasstirred at room temperature for 48 hours. The reaction mixture wasconcentrated in vacuo and the residue was purified by silica gelchromatography (0-50% ethyl acetate/hexanes) to provide methyl3,5-difluoropyridine-4-carboxylate (2.332 g, 40%) as a clear, colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 2H), 4.01 (s, 3H) ppm.

Step 2: Methyl3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylate

Methyl 3,5-difluoropyridine-4-carboxylate (1.012 g, 5.846 mmol),2-methoxy-4-(trifluoromethoxy)phenol (1.354 g, 6.505 mmol) and cesiumcarbonate (2.48 g, 7.61 mmol) were combined in DMF (22 mL). The mixturewas stirred at 50° C. for 3 hours. The reaction mixture was cooled,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water (2×), dried by passing through a phase separationcartridge, and concentrated in vacuo. Silica gel chromatography (0-70%ethyl acetate/hexanes) provided methyl3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylate(2.02 g, 96%) as a clear oil. ESI-MS m/z calc. 361.06, found 362.0(M+1)+; retention time (Method F): 0.98 minutes (1.5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 8.53 (d, J=0.4 Hz, 1H), 8.04 (s, 1H), 7.34-7.22 (m,3H), 7.00 (ddq, J=8.9, 2.4, 1.2 Hz, 2H), 3.87 (s, 4H), 3.80 (d, J=12.8Hz, 1H), 3.80 (s, 4H), 3.34 (s, OH), 2.89 (s, 1H), 2.74 (d, J=0.7 Hz,1H) ppm.

Step 3:3-Fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylicAcid

Methyl3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylate(250 mg, 0.692 mmol) and aqueous NaOH (370 μL of 2 M, 0.7400 mmol) inTHF (7 mL) were stirred at 71° C. for 72 hours. The reaction mixture wasconcentrated in vacuo to provide3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylicacid (240 mg, 100%). ESI-MS m/z calc. 347.0417, found 347.9 (M+1)+;retention time (Method F): 0.55 minutes (1.5 minute run).

Step 4:N-(6-Bromo-5-fluoro-2-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide

To a solution of3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylicacid (240 mg, 0.691 mmol) in dichloromethane (5 mL) at 0° C. was addedDMF (24 mg, 0.33 mmol) and oxalyl chloride (290 mg, 200 μL, 2.29 mmol)dropwise. The reaction mixture was stirred for 2 hours then concentratedin vacuo to afford3-fluoro-5-(2-methoxy-4-(trifluoromethoxy)phenoxy)isonicotinoyl chlorideas a pale yellow oil Conversion to the acid chloride was monitoredthrough formation of the methyl ester following methanol quench. The oilwas dissolved in dichloromethane (5 mL) and added dropwise to a solutionof 6-bromo-5-fluoro-pyridin-2-amine (130 mg, 0.681 mmol) andtriethylamine (436 mg, 601 μL, 4.31 mmol) in dichloromethane (3 mL) at0° C. The resulting mixture was allowed to warm to room temperature andstirred for 16 hours. Silica gel chromatography (0-100% ethylacetate/petroleum ether) providedN-(6-bromo-5-fluoro-2-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(170 mg, 47%) as an off-white waxy solid. ESI-MS m/z calc. 518.99, found521.9 (M+1)+; 519.8 (M−1)−; retention time (Method F): 1.06 minutes (1.5minute run). ¹H NMR (400 MHz, CDCl₃) δ 9.47 (s, 1H), 8.35 (dd, J=8.8,3.3 Hz, 1H), 8.34 (s, 1H), 8.00 (s, 1H), 7.51 (dd, J=8.8, 6.9 Hz, 1H),7.34-7.26 (m, 1H), 6.93 (dtt, J=3.8, 2.6, 1.3 Hz, 3H), 3.94 (s, 3H) ppm.

Step 5: Methyl3-fluoro-6-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]pyridine-2-carboxylate

In a pressure tubeN-(6-bromo-5-fluoro-2-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(50 mg, 0.096 mmol) was dissolved in methanol (2.3 mL) and triethylamine(21 mg, 29 μL, 0.21 mmol) and Pd(dppf)Cl₂.DCM (18 mg, 0.022 mmol) wereadded. Carbon monoxide was bubbled through the reaction mixture for 5minutes. The reaction mixture was sealed and heated to 75° C. for 16hours. The mixture was cooled and concentrated in vacuo. Silica gelchromatography (0-90% ethyl acetate/petroleum ether) provided methyl3-fluoro-6-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]pyridine-2-carboxylate(20 mg, 42%). ESI-MS m/z calc. 499.08, found 500.2 (M+1)+; 498.2 (M−1)−;retention time (Method F): 0.97 minutes (1.5 minute run). ¹H NMR (400MHz, CDCl₃) δ 9.35 (s, 1H), 8.63 (dd, J=9.1, 3.2 Hz, 1H), 8.38 (s, 1H),8.03 (s, 1H), 7.66 (t, J=9.1 Hz, 1H), 7.26 (m, 1H), 6.97-6.89 (m, 1H),6.92 (s, 1H), 3.98 (d, J=13.4 Hz, 6H) ppm.

Step 6:3-Fluoro-6-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]pyridine-2-carboxamide(164)

Methyl3-fluoro-6-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]pyridine-2-carboxylate(20 mg, 0.04 mmol) was dissolved in a solution of ammonia (2 mL of 7 Min methanol, 14 mmol) and stirred at 45° C. in a sealed tube overnight.The reaction mixture was cooled and concentrated in vacuo. HPLCpurification (37-100% acetonitrile/0.1% ammonium hydroxide) andlyophilization of product fractions provided3-fluoro-6-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]pyridine-2-carboxamide(3 mg, 15%). ESI-MS m/z calc. 484.08, found 484.91 (M+1)+; 482.96(M−1)−; retention time (Method E): 2.66 minutes (5 minute run). ¹H NMR(400 MHz, CD₃OD) δ 8.44 (dd, J=9.1, 3.1 Hz, 1H), 8.39 (s, 1H), 7.97 (s,1H), 7.81 (t, J=9.5 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.6 Hz,1H), 6.93 (ddt, J=8.8, 2.0, 1.0 Hz, 1H), 3.82 (s, 3H) ppm.

Example 120N-(2-Carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(165)

This compound was made in an analogous fashion to Example 119, step 4,except employing 4-aminopyridine-2-carboxamide in the amide formationstep. The yield of the desired product after purification was 4 mg (3%).ESI-MS m/z calc. 466.09, found 467.05 (M+1)+; retention time (Method E):2.64 minutes (5 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H),8.55 (d, J=10.9 Hz, 2H), 8.27 (d, J=2.2 Hz, 1H), 8.08 (d, J=14.7 Hz,2H), 7.81-7.75 (m, 1H), 7.66 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.19 (d,J=2.7 Hz, 1H), 6.98 (ddq, J=8.7, 2.4, 1.2 Hz, 1H), 3.78 (s, 3H) ppm.

Example 121N-(3-Carbamoyl-4-fluoro-phenyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(117)

Step 1:N-(3-carbamoyl-4-fluoro-phenyl)-3,5-difluoro-pyridine-4-carboxamide

To a solution of 3,5-difluoropyridine-4-carboxylic acid (200 mg, 0.880mmol) in dichloromethane (2.6 mL) at 0° C. was added DMF (21 μL, 0.27mmol) and oxalyl chloride (250 μL, 2.87 mmol) dropwise. The reaction wasstirred for 2 hours then concentrated in vacuo. The residue wasdissolved in dichloromethane (2.6 mL), cooled to 0° C. and treated with5-amino-2-fluoro-benzamide hydrochloride (280 mg, 1.23 mmol) andtriethylamine (740 μL, 5.28 mmol). The reaction mixture was allowed tocome to room temperature over 2 hours, then was diluted with water andextracted with dichloromethane (2×10 mL). The combined organics weredried using a phase separation cartridge and concentrated in vacuo toprovideN-(3-carbamoyl-4-fluoro-phenyl)-3,5-difluoro-pyridine-4-carboxamide (130mg, 50%). ESI-MS m/z calc. 295.06, found 295.9 (M+1)+; 293.9 (M−1)−;retention time (Method F): 0.53 minutes (1.5 minute run).

Step 2:N-(3-Carbamoyl-4-fluoro-phenyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(117)

N-(3-carbamoyl-4-fluoro-phenyl)-3,5-difluoro-pyridine-4-carboxamide (130mg, 0.440 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (102 mg, 0.492mmol) and Cs₂CO₃ (185 mg, 0.570 mmol) were combined in DMF (1.3 mL). Themixture was stirred at room temperature for 30 days. The reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed further with water, dried by passing through aphase separation cartridge and concentrated in vacuo. HPLC purification(37-100% acetonitrile/0.1% ammonium hydroxide) providedN-(3-carbamoyl-4-fluoro-phenyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(6.2 mg, 1%). ESI-MS m/z calc. 483.09, found 483.76 (M+1)+; retentiontime (Method E): 2.65 minutes (5 minute run). ¹H NMR (400 MHz, CD₃OD) δ8.38 (s, 1H), 8.04 (dd, J=6.4, 2.8 Hz, 1H), 7.97 (s, 1H), 7.89 (ddd,J=9.0, 4.4, 2.8 Hz, 1H), 7.32-7.20 (m, 2H), 7.08 (d, J=2.6 Hz, 1H),6.98-6.89 (m, 1H), 3.82 (s, 3H) ppm.

Example 1224-[[3-Fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(151)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-3,5-difluoro-pyridine-4-carboxamide

This compound was made in an analogous fashion to Example 121, Step 1,except employing 2-bromo-5-methyl-pyridin-4-amine in the amide formationstep. The yield of the desired product after purification was 430 mg(60%). ESI-MS m/z calc. 326.98, found 329.9 (M+1)+; 325.8 (M−1)−;retention time (Method E): 1.51 minutes (5 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 10.77 (s, 1H), 8.76 (s, 2H), 8.33-8.27 (m, 1H), 8.10 (s, 1H),2.23 (d, J=0.8 Hz, 3H) ppm.

Step 2:N-(2-Bromo-5-methyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide

N-(2-bromo-5-methyl-4-pyridyl)-3,5-difluoro-pyridine-4-carboxamide (125mg, 0.381 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (90 mg, 0.43 mmol)and Cs₂CO₃ (160 mg, 0.491 mmol) were combined in DMF (3 mL) and stirredat 61° C. for 72 hours. The reaction mixture was concentrated in vacuoand purified by silica gel chromatography (0-90% ethyl acetate/hexanes)to provideN-(2-bromo-5-methyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(108 mg, 55%). ESI-MS m/z calc. 515.01, found 518.1 (M+1)+; retentiontime (Method F): 1.0 minutes (1.5 minute run). ¹H NMR (400 MHz, CDCl₃) δ8.54 (s, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.94 (s, 1H),7.25 (dd, J=25.6, 9.0 Hz, 1H), 7.00-6.86 (m, 2H), 3.81 (s, 3H), 2.15 (t,J=1.9 Hz, 3H) ppm.

Step 3: Methyl4-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate

This compound was made in an analogous fashion to Example 119, Step 5,except employingN-(2-bromo-5-methyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamidein the carbonylation step. The yield of the desired product afterpurification was 15 mg (30%). ESI-MS m/z calc. 495.10, found 496.0(M+1)+; 493.9 (M−1)−; retention time (Method F): 0.88 minutes (1.5minute run time).

Step 4:4-[[3-Fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(151)

This compound was made in an analogous fashion to Example 119, Step 6,except employing methyl4-[[3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylatein the carboxamide formation step. The yield of the desired productafter purification was 2 mg (13%). ESI-MS m/z calc. 480.11, found 481.21(M+1)+; retention time (Method E): 2.66 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.56 (s, 1H), 8.45 (d, J=19.7 Hz,2H), 8.04 (d, J=11.0 Hz, 2H), 7.61 (s, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.23(s, 1H), 7.01 (d, J=9.1 Hz, 1H), 3.82 (s, 3H), 2.28 (d, J=8.9 Hz, 3H)ppm.

Example 1235-[[4-Chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(204)

5-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(185, 45 mg, 0.089 mmol) and sodium methoxide (900 μL of 0.5 M inmethanol, 0.45 mmol) were combined in a microwave vial and the sealedreaction mixture heated at 80° C. for 16 hours. The reaction was cooled,treated with 2 drops of trifluoroacetic acid, and diluted with DMSO (2mL). HPLC purification (1-99% acetonitrile/0.1% ammonia hydroxide) andfreeze-drying of product fractions provided5-[[4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(20 mg, 42%) as an off-white solid. ESI-MS m/z calc. 511.08, found 512.0(M+1)+; 510.0 (M−1)−; retention time (Method E): 3.12 minutes (5 minuterun). ¹H NMR (500 MHz, DMSO-d6) δ 13.21 (s, 1H), 11.13 (d, J=2.4 Hz,1H), 10.55 (dd, J=8.6, 2.5 Hz, 1H), 10.33-10.24 (m, 2H), 9.80 (d, J=2.8Hz, 1H), 9.53-9.44 (m, 2H), 9.33-9.23 (m, 2H), 8.62 (d, J=1.7 Hz, 1H),6.15 (s, 3H), 6.07 (s, 3H) ppm.

Example 1244-[[4-Chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(133)

Step 1:4-Chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde

A mixture of 2-methoxy-4-(trifluoromethoxy)phenol (1.15 g, 5.53 mmol),Cs₂CO₃ (2.20 g, 6.75 mmol) and 4-chloro-2-fluoro-6-methoxy-benzaldehyde(1.00 g, 5.30 mmol) in DMF (9 mL) was stirred for 16 hours at roomtemperature. The reaction mixture was concentrated and the residue waspartitioned between water and dichloromethane. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-50% ethyl acetate/petroleum ether) provided4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde(1.880 g, 94%) as a white solid. ESI-MS m/z calc. 376.03, found 377.1(M+1)+; retention time (Method F): 1.07 minutes (1.5 minute run). ¹H NMR(500 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.28-7.21 (m, 2H), 7.06-6.98 (m,2H), 6.26 (d, J=1.8 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 3H) ppm.

Step 2:4-Chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic Acid

A mixture of4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde(1.880 g, 4.991 mmol), sodium dihydrogenphosphate hydrate (0.630 g, 5.25mmol) and 2-methyl-2-butene (10 mL of 2 M in THF, 20 mmol) in tert-butylalcohol (17 mL)/water (8.5 mL) at 0° C. was treated with sodium chlorite(0.670 g, 5.926 mmol) portionwise over 30 minutes. The mixture wasallowed to warm to room temperature then stirred for 16 hours. Thereaction mixture was acidified to pH1-2 using 2 M HCl and partitionedwith dichloromethane. The organic layer was separated, dried using aphase separation cartridge and concentrated in vacuo to afford4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(1.890 g, 96%) as a white solid. ESI-MS m/z calc. 392.03, found 393.1(M+1)+; 391.1 (M−1)−; retention time (Method F): 0.69 minutes (1.5minute run). ¹H NMR (500 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.21 (d, J=2.7Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 6.98 (ddq, J=8.8, 2.4, 1.1 Hz, 1H),6.95 (d, J=1.7 Hz, 1H), 6.28 (d, J=1.7 Hz, 1H), 3.85 (s, 3H), 3.81 (s,3H) ppm.

Step 3:N-(2-Bromo-5-methyl-4-pyridyl)-4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide

To a solution of4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(320 mg, 0.766 mmol) in dichloromethane (5.3 mL) at 0° C. was added DMF(7 μL, 0.09 mmol) and oxalyl chloride (225 μL, 2.58 mmol) dropwise. Thereaction mixture was allowed to warm to room temperature over 3.5 hoursthen concentrated in vacuo. The residue was dissolved in dichloromethane(5.3 mL), cooled to 0° C. and treated with2-bromo-5-methyl-pyridin-4-amine (186 mg, 0.995 mmol) and triethylamine(565 μL, 4.05 mmol). The resulting mixture was allowed to warm to roomtemperature and stirred for 16 hours. The reaction mixture was dilutedwith water (10 mL) and extracted with dichloromethane (2×10 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedin vacuo. Silica gel chromatography (20-50% ethyl acetate/petroleumether) providedN-(2-bromo-5-methyl-4-pyridyl)-4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(300 mg, 70%) as a yellow oil. ESI-MS m/z calc. 560.00, found 563.0(M+1)+; retention time (Method F): 1.1 minutes (1.5 minute run).

Step 4: Methyl4-[[4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tubeN-(2-bromo-5-methyl-4-pyridyl)-4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(300 mg, 0.497 mmol) was dissolved in methanol (10 mL) and triethylamine(107 mg, 1.06 mmol) and Pd(dppf)Cl₂.DCM (82 mg, 0.10 mmol) was added.Carbon monoxide was bubbled through the vigorously stirring reactionmixture for 5 minutes. The reaction vessel was sealed and heated to 75°C. for 16 hours. The reaction mixture was filtered through a pad ofCelite eluting with methanol and concentrated in vacuo. Silica gelchromatography (30-80% ethyl acetate/petroleum ether) provided methyl4-[[4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(98 mg, 36%) as a yellow oil. ESI-MS m/z calc. 540.09, found 541.0(M+1)+; retention time (Method F): 1.02 minutes (1.5 minute run).

Step 5:4-[[4-Chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(133)

A mixture of methyl4-[[4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(98 mg, 0.18 mmol) and ammonia (5 mL of 4 M in methanol, 20 mmol) wasstirred at room temperature for 16 hours then concentrated in vacuo.HPLC purification (37-100% acetonitrile/0.1% ammonium hydroxide)provided4-[[4-chloro-2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(39.1 mg, 41%) as a white solid. ESI-MS m/z calc. 525.09, found 526.0(M+1)+; retention time (Method E): 3.31 minutes (5 minute run). ¹H NMR(500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.44 (d, J=13.2 Hz, 2H), 8.03 (d,J=2.9 Hz, 1H), 7.56 (d, J=2.9 Hz, 1H), 7.32-6.91 (m, 4H), 6.33 (d, J=1.7Hz, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 2.27 (s, 3H) ppm.

Example 1254-[[2,4-Dichloro-6-(4-fluorophenoxy)benzoyl]amino]pyridine-2-carboxamide(177)

To 4-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide(prepared as described in Example 112, step 1, 45 mg, 0.14 mmol) in DMF(1 mL) was added 4-fluorophenol (15 mg, 0.13 mmol) followed by K₂CO₃ (57mg, 0.41 mmol). The reaction was heated at 80° C. for 30 minutes. HPLCpurification (1-99% acetonitrile/5 mM HCl) provided4-[[2,4-dichloro-6-(4-fluorophenoxy)benzoyl]amino]pyridine-2-carboxamide(38 mg, 66%). ESI-MS m/z calc. 419.02, found 419.95 (M+1)+; retentiontime (Method B): 1.63 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.35 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.11(d, J=2.8 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.67 (d, J=2.8 Hz, 1H),7.60 (d, J=1.8 Hz, 1H), 7.33-7.25 (m, 2H), 7.25-7.18 (m, 2H), 6.93 (d,J=1.8 Hz, 1H) ppm.

Example 1265-[[2,4-Dichloro-6-(4-fluorophenoxy)benzoyl]amino]pyridine-2-carboxamide(181)

To a solution of5-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxamide (preparedas described in Example 111, Step 3, 44 mg, 0.134 mmol) in DMF (0.5 mL)was added 4-fluorophenol (15 mg, 0.13 mmol) followed by K₂CO₃ (56 mg,0.40 mmol). The reaction was heated at 80° C. for 1 hour, then dilutedwith DMSO (0.5 mL) and filtered. Purification by HPLC (1-99%acetonitrile/5 mM HCl) provided5-[[2,4-dichloro-6-(4-fluorophenoxy)benzoyl]amino]pyridine-2-carboxamide(26.7 mg, 47%). ESI-MS m/z calc. 419.02, found 419.9 (M+1)+; retentiontime (Method B): 1.63 minutes (3 minutes). ¹H NMR (400 MHz, DMSO-d6) δ11.25 (s, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.26 (dd, J=8.5, 2.5 Hz, 1H),8.04 (d, J=8.6 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.60 (d, J=1.7 Hz, 1H),7.57 (d, J=3.2 Hz, OH), 7.28 (t, J=8.7 Hz, 2H), 7.21 (dd, J=9.2, 4.5 Hz,2H), 6.94 (d, J=1.7 Hz, 1H) ppm.

Example 1274-[[2-Methoxy-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(146)

To4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(59 mg, 0.11 mmol, prepared as described in Example 28) was added asolution of sodium methoxide (1 mL of 0.5 M in methanol, 0.5 mmol) andthe reaction was heated at 80° C. for 23 hours. The reaction mixture wasfiltered and the resulting solid was purified by HPLC (10-99%acetonitrile/water) to provide4-[[2-methoxy-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(32.6 mg, 55%). ESI-MS m/z calc. 562.13, found 563.0 (M+1)+; retentiontime (Method C): 2.51 minutes (5 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.48 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.09-8.01 (m, 1H), 7.68 (d,J=9.0 Hz, 1H), 7.65-7.57 (m, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.8Hz, 1H), 7.10-7.00 (m, 1H), 6.52 (d, J=8.9 Hz, 1H), 3.98 (s, 3H), 2.32(s, 3H) ppm.

Example 128N-(3-Carbamoyl-4-fluoro-phenyl)-6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzamide(54)

Step 1:6-[(6-Chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoicAcid

To a pressure flask was added6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (1.80 g, 6.27 mmol),6-chloro-2-methoxy-pyridin-3-ol (1.00 g, 6.27 mmol), cesium carbonate(4.0 g, 12 mmol) and toluene (30 mL). The reaction mixture was bubbledwith N₂ for 10 minutes, then copper (I) iodide (240 mg, 1.26 mmol) wasadded. The flask was flushed with N₂, sealed, and heated at 100° C. withvigorous stirring for 1 hour. The mixture was allowed to cool to roomtemperature then diluted with ethyl acetate and water. The water layerwas acidified with 1 M HCl (30 mL) and the product extracted into theethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo to a dark green oil. To theoil was added minimal amount of dichloromethane and hexanes to form aprecipitate. The solid was filtered, washed with hexanes and dried toprovide6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (1.3 g, 57%). ESI-MS m/z calc. 365.01, found 365.9 (M+1)+;retention time (Method A): 0.67 minutes (1.2 minute run). ¹H NMR (400MHz, DMSO-d6) δ 14.20 (br s, 1H), 7.86-7.57 (m, 2H), 7.19 (d, 1H),6.86-6.78 (m, 1H), 3.86 (s, 3H) ppm.

Step 2:6-[(6-Chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride

To a suspension of6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (600 mg, 1.64 mmol) and DMF (5 μL, 0.06 mmol) in dichloromethane (9mL) at 0° C. was added oxalyl chloride (0.7 mL, 8 mmol) dropwise. Thereaction was allowed to come to room temperature and stirred for 30minutes. Conversion to the desired acid chloride was monitored by UPLCvia test for morpholine adduct formation. The reaction mixture wasconcentrated under reduced pressure then co-evaporated withdichloromethane (3×55 mL) to afford6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride.

Step 3:N-(3-Carbamoyl-4-fluoro-phenyl)-6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzamide(54)

5-Amino-2-fluoro-benzamide (40 mg, 0.26 mmol) was suspended indichloromethane (1 mL) and DIEA (101 mg, 136 μL, 0.781 mmol) and cooledto 0° C., then treated with a cold solution of6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride (100 mg, 0.260 mmol) in dichloromethane (1 mL). The reactionwas then allowed to warm to room temperature and stirred for 16 hours.The reaction was concentrated in vacuo, dissolved in DMSO and purifiedby HPLC (10-99% acetonitrile/5 mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzamide(5.3 mg, 4.06%). ESI-MS m/z calc. 501.05, found 502.0 (M+1)+; retentiontime (Method B): 1.66 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.03 (s, 1H), 7.98 (dd, J=6.3, 2.8 Hz, 1H), 7.82-7.74 (m, 3H), 7.72(d, J=8.1 Hz, 1H), 7.69 (s, 1H), 7.30 (dd, J=10.1, 8.9 Hz, 1H), 7.19 (d,J=8.1 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H), 3.86 (s, 3H) ppm.

Example 129N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-4-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(216)

Step 1: 5-Bromo-1-fluoro-3-methoxy-2-(trifluoromethyl)benzene

To a solution of 5-bromo-1,3-difluoro-2-(trifluoromethyl)benzene (1.0 g,3.8 mmol) in DMF (10 mL) at 0° C. was added a solution of sodiummethoxide (12 mL of 0.5 M in methanol, 6 mmol) dropwise. The coolingbath was removed and the reaction mixture was stirred for 2 days at roomtemperature. The reaction mixture was diluted with dichloromethane andwashed with water. The separated organic layer was washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography using hexanes as eluent provided5-bromo-1-fluoro-3-methoxy-2-(trifluoromethyl)benzene (600 mg, 57%) as acolorless oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.49-7.29 (m, 2H), 3.94 (s,3H) ppm. ¹⁹F NMR (376 MHz, DMSO-d6) δ −55.27 (d, J=29.6 Hz),−111.65-−112.01 (m) ppm.

Step 2: Ethyl 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoate

A solution of 5-bromo-1-fluoro-3-methoxy-2-(trifluoromethyl)benzene(1.19 g, 4.36 mmol) in THF (12 mL) was cooled to −78° C. (dryice/acetone bath) and a solution of LDA (2.1 mL of 2 M, 4.2 mmol) wasadded dropwise while maintaining the internal temperature below −70° C.The reaction mixture was stirred at −70° C. for 30 minutes, then ethylcarbonochloridate (1 mL, 10 mmol) was added dropwise maintaining theinternal temperature below −70° C. The reaction mixture was allowed towarm to room temperature and was stirred for 1 hour. The reactionmixture was quenched with saturate aqueous NH₄Cl solution and extractedwith ethyl acetate. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-5% ethylacetate/hexanes) provided ethyl6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoate (585 mg, 39%).ESI-MS m/z calc. 343.96, found 347.0 (M+1)+; retention time (Method B):1.58 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 7.53 (dd,J=1.7, 0.8 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.99 (s, 3H), 1.31 (t, J=7.1Hz, 3H) ppm.

Step 3: 6-Bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic Acid

To a solution of ethyl6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoate (580 mg, 1.68mmol) in methanol (6 mL) was added an aqueous NaOH (6 mL of 6 M, 36mmol) and the reaction mixture was stirred for 24 hours. The reactionmixture was cooled to 0° C. and quenched with 6 M HCl. The resultingprecipitate was filtered and washed with water. The solid was dissolvedin dichloromethane, dried over MgSO₄, filtered and concentrated in vacuoto provide 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid(456 mg, 86%). ESI-MS m/z calc. 315.93, found 319.0 (M+2)+; retentiontime (Method B): 1.03 minutes (3 minute run).

Step 4:2-Fluoro-4-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicAcid

To a pressure vessel were added6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid (285 mg,0.899 mmol), 4-(trifluoromethoxy)phenol (145 mg, 0.814 mmol), Cs₂CO₃(313 mg, 0.961 mmol) and toluene (3 mL). The reaction mixture wasbubbled with N₂ for 10 minutes then treated with copper (I) iodide (60mg, 0.32 mmol). The flask was flushed with N₂, sealed, and heated at100° C. with vigorous stirring for 4 hours. The mixture was cooled toroom temperature, acidified with 1 M HCl, filtered and the aqueous layerwas extracted with ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Silica gelcolumn chromatography (0-100% ethyl acetate/hexanes) provided2-fluoro-4-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (213 mg, 57%) ESI-MS m/z calc. 414.03, found 415.1 (M+1)+;retention time (Method B): 1.79 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 13.69 (s, 1H), 7.42 (dq, J=7.7, 1.0 Hz, 2H), 7.26-7.17 (m,2H), 6.72 (s, 1H), 3.82 (s, 3H) ppm.

Step 5:N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-4-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(216)

To a flask charged with2-fluoro-4-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (205 mg, 0.495 mmol), 5-amino-2-fluoro-benzamide (81 mg, 0.53 mmol)and HATU (230 mg, 0.605 mmol) in DMF (2.5 mL) was added DIEA (300 μL,1.72 mmol) and the reaction mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with water and the aqueouslayer was extracted with ethyl acetate. The organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo. Thecrude material was purified by HPLC (1-99% acetonitrile/5 mM HCl) toprovideN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-4-methoxy-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(110 mg, 38%). ESI-MS m/z calc. 550.07, found 551.3 (M+1)+; retentiontime (Method B): 1.54 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.82 (s, 1H), 7.90 (dd, J=6.4, 2.8 Hz, 1H), 7.76-7.62 (m, 3H),7.44-7.35 (m, 2H), 7.30-7.19 (m, 3H), 6.69 (s, 1H), 3.83 (s, 3H) ppm.

Example 1304-Benzyloxy-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(215)

Step 1: 1-Benzyloxy-5-bromo-3-fluoro-2-(trifluoromethyl)benzene

To a solution of phenylmethanol (0.800 mL, 7.73 mmol) in THF (12 mL) wasadded NaH (0.310 g of 60% w/w, 7.75 mmol) portionwise at 0° C. Thereaction mixture was stirred for 1 hour and then a solution of5-bromo-1,3-difluoro-2-(trifluoromethyl)benzene (2.00 g, 7.66 mmol) inTHF (12 mL) was added slowly while maintaining the internal temperaturebelow 40° C. The reaction mixture was stirred for 2 hours. The reactionmixture was quenched with water and the aqueous layer was extracted withdichloromethane. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel column chromatography using hexanes aseluent provided 1-benzyloxy-5-bromo-3-fluoro-2-(trifluoromethyl)benzene(1.31 g, 49%). ¹H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 7.46-7.32 (m,6H), 5.32 (s, 2H) ppm.

Step 2: Ethyl 4-benzyloxy-6-bromo-2-fluoro-3-(trifluoromethyl)benzoate

To a solution of 1-benzyloxy-5-bromo-3-fluoro-2-(trifluoromethyl)benzene(1.30 g, 3.72 mmol) in THF (13 mL) at −78° C. was added a solution ofLDA (1.9 mL of 2 M, 3.8 mmol) dropwise while maintaining the internaltemperature below −70° C., and the reaction mixture was stirred at −70°C. for 30 minutes. Ethyl chloroformate (0.900 mL, 9.41 mmol) was addeddropwise maintaining the internal temperature below −70° C. Theresultant reaction mixture was allowed to warm to room temperature andstirred for 1 hour. The reaction mixture was quenched with a saturatedaqueous NH₄Cl solution and the aqueous layer was extracted with ethylacetate. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-5% ethylacetate/hexanes) provided ethyl4-benzyloxy-6-bromo-2-fluoro-3-(trifluoromethyl)benzoate (860 mg, 55%).ESI-MS m/z calc. 419.99, found 423.0 (M+1)+; retention time (Method B):2.16 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J=1.5Hz, 1H), 7.46-7.40 (m, 4H), 7.37 (ddt, J=5.5, 4.5, 3.6 Hz, 1H), 5.38 (s,2H), 4.38 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H) ppm.

Step 3: 4-Benzyloxy-6-bromo-2-fluoro-3-(trifluoromethyl)benzoic Acid

To a solution of ethyl4-benzyloxy-6-bromo-2-fluoro-3-(trifluoromethyl)benzoate (0.900 g, 2.14mmol) in methanol (10 mL) and water (10 mL) was added NaOH (2.0 g, 50mmol) and the reaction mixture was stirred at room temperature for 20hours. The solvent was evaporated and the crude material was taken up inwater, cooled to 0° C. and acidified with 6 M HCl. The aqueous layer wasextracted with ethyl acetate. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. Silica gel column chromatography(0-50% ethyl acetate/hexanes) provided4-benzyloxy-6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (170 mg,20%). ESI-MS m/z calc. 391.96, found 395.0 (M+1)+; retention time(Method B): 1.72 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ14.16 (s, 1H), 7.61 (s, 1H), 7.45-7.34 (m, 5H), 5.37 (s, 2H) ppm.

Step 4:4-Benzyloxy-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicAcid

To a microwave vial was added4-benzyloxy-6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (165 mg,0.420 mmol), 4 4-(trifluoromethoxy)phenol (0.07 mL, 0.54 mmol), Cs₂CO₃(150 mg, 0.460 mmol) and toluene (4 mL). The reaction mixture wasbubbled with N₂ for 10 minutes then treated with copper (I) iodide (35mg, 0.18 mmol). The flask was flushed with N₂, sealed, and heated at100° C. with vigorous stirring for 4 hours. The mixture acidified with 1M HCl, filtered and the aqueous layer was extracted with ethyl acetate.The organic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-50% ethylacetate/hexanes) provided4-benzyloxy-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (93 mg, 45%). ESI-MS m/z calc. 490.06, found 491.1 (M+1)+;retention time (Method B): 2.06 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 13.70 (s, 1H), 7.44-7.32 (m, 5H), 7.29 (dd, J=7.7, 1.9 Hz,2H), 7.18-7.10 (m, 2H), 6.75 (s, 1H), 5.22 (s, 2H) ppm.

Step 5:4-Benzyloxy-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(215)

To a flask charged with4-benzyloxy-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (90 mg, 0.18 mmol), 5-amino-2-fluoro-benzamide (34 mg, 0.22 mmol)and HATU (86 mg, 0.23 mmol) in DMF (1 mL) was added DIEA (0.100 mL,0.574 mmol) and the reaction mixture was stirred at room temperature for20 hours. The reaction mixture was diluted with water and the resultingprecipitate was filtered and washed with water. The residue wasdissolved in dichloromethane, dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-50% ethylacetate/hexanes) provided4-benzyloxy-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(100 mg, 87%). ESI-MS m/z calc. 626.10, found 627.3 (M+1)+; retentiontime (Method B): 2.01 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.82 (s, 1H), 7.90 (dd, J=6.4, 2.8 Hz, 1H), 7.73-7.63 (m, 3H),7.44-7.32 (m, 5H), 7.29-7.15 (m, 5H), 6.68 (s, 1H), 5.25 (s, 2H) ppm.

Example 1314-[[6-(2,4-Dimethoxyphenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(195)

Step 1: 6-Bromo-2-fluoro-3-(trifluoromethyl)benzoyl chloride

To a solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5.40g, 18.8 mmol) and DMF (126 mg, 1.72 mmol) in dichloromethane (54 mL) at0° C. was added oxalyl chloride (11.5 g, 90.3 mmol) dropwise. Themixture was allowed to warm to room temperature and stirred for 5 hoursunder N₂ atmosphere. The solvent was evaporated in vacuo to afford6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl chloride. The intermediatewas used in the next step without further purification.

Step 2:4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of 4-aminopyridine-2-carboxamide (2.56 g, 18.7 mmol) andDIEA (6.03 g, 46.7 mmol) in dichloromethane (29 mL) at 0° C. was added asolution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl chloride (5.7 g,18.7 mmol) in dichloromethane (29 mL) dropwise. The reaction mixture wasallowed to warm to room temperature and stirred for 16 hours. Ethylacetate (150 mL) was added to the reaction mixture followed by theaddition of water. The organic layer was separated, dried over Na₂SO₄,and concentrated in vacuo. Silica gel chromatography (1-10%methanol/dichloromethane) provided4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(800 mg, 11%). ESI-MS m/z calc. 404.97, found 408.2 (M+1)+; retentiontime Method (B): 0.58 minutes (3 minute run).

Step 3:4-[[6-(2,4-Dimethoxyphenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(195)

To a microwave vial were added4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(50 mg, 0.12 mmol), Cs₂CO₃ (80 mg, 0.25 mmol), 2,4-dimethoxyphenol (19mg, 0.12 mmol) and toluene (500 μL, degassed via bubbling with N₂). Themixture was bubbled with N₂ and then treated with copper (I) iodide (13mg, 0.066 mmol). The vial was sealed and the reaction stirred at 100° C.for 20 minutes. The reaction was diluted with ethyl acetate and water.The organic layer was separated, dried over Na₂SO₄ and concentrated invacuo. HPLC purification (1-99% acetonitrile/5 mM HCl) provided4-[[6-(2,4-dimethoxyphenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(9.6 mg, 16%). ESI-MS m/z calc. 479.11, found 480.2 (M+1)+; retentiontime (Method B): 1.55 minutes (3 minute run).

Example 1324-[[2-Fluoro-6-[4-methoxy-2-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(196)

In a microwave vial were combined4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(prepared as described in Example 131, 50 mg, 0.12 mmol), Cs₂CO₃ (80 mg,0.25 mmol), 4-methoxy-2-(trifluoromethoxy)phenol (26 mg, 0.12 mmol) andtoluene (0.5 mL, degassed by N₂ bubbling). The mixture was furtherbubbled with N₂, then copper (I) iodide (14 mg, 0.074 mmol) was addedand the reaction was stirred at 100° C. for 20 minutes. The reaction wasdiluted with ethyl acetate and water. The layers were separated and theorganic layer was concentrated in vacuo. The crude material wasdissolved in DMSO (2 mL) and purified by HPLC (1-99% acetonitrile/5 mMHCl) to obtain4-[[2-fluoro-6-[4-methoxy-2-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(17.6 mg, 27%). ESI-MS m/z calc. 533.08, found 534.4 (M+1)+; retentiontime (Method B): 1.69 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.45 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.11(d, J=2.9 Hz, 1H), 7.99-7.73 (m, 2H), 7.67 (d, J=2.9 Hz, 1H), 7.42 (d,J=9.0 Hz, 1H), 7.29-6.94 (m, 2H), 6.77 (d, J=8.9 Hz, 1H), 3.82 (s, 3H)ppm. ¹⁹F NMR (376 MHz, DMSO) δ −57.29, −59.21, −59.25, −117.27, −117.30,−117.33, −117.34, −117.36 ppm.

Example 1334-[[6-[2-(Difluoromethoxy)-4-fluoro-phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(208)

Step 1: 2-(Difluoromethoxy)-4-fluoro-1-methoxy-benzene

A mixture of 5-fluoro-2-methoxy-phenol (1.00 g, 7.04 mmol), sodium2-chloro-2,2-difluoro-acetate (2.68 g, 17.6 mmol) and cesium carbonate(4.58 g, 14.1 mmol) in DMF (14 mL) and water (1.5 mL) was heated at 100°C. for 16 hours. The reaction mixture was diluted with dichloromethane,filtered, and the filtrate was washed with water and brine. The organiclayer was dried over MgSO₄, concentrated in vacuo and purified by silicagel chromatography (0-20% ethyl acetate/hexanes) to provide2-(difluoromethoxy)-4-fluoro-1-methoxy-benzene (590 mg, 44%) as acolorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 6.99-6.86 (m, J=6.5, 5.1 Hz,3H), 6.56 (t, J=74.7 Hz, 1H), 3.86 (s, 3H) ppm.

Step 2:4-[[2,6-Difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of 2,6-difluoro-3-(trifluoromethyl)benzoic acid (250 mg,1.11 mmol) in dichloromethane (4 mL) at 0° C. was added DMF (10 μL, 0.13mmol) followed by the dropwise addition of oxalyl chloride (0.250 mL,2.87 mmol). The reaction mixture was stirred at 0° C. for 40 minutes.The solvent was removed in vacuo to afford a gummy solid. The solid wasdissolved in dichloromethane and added dropwise to a solution of4-aminopyridine-2-carboxamide (152 mg, 1.11 mmol) and DIEA (0.40 mL, 2.3mmol) in NMP (3 mL) at 0° C. The reaction mixture was allowed to warm toroom temperature slowly with ice-bath in place and stirred for 16 hours.The reaction mixture was poured onto ice, diluted with dichloromethaneand stirred for 30 minutes. The organic layer was separated,concentrated in vacuo, and the resulting brown oil was partitionedbetween ethyl acetate and water. The layers were separated and theorganic layer was further washed with water. The organic layer was dried(by passing through a phase separation cartridge) and concentrated invacuo. Purification by silica gel chromatography (0-100% ethylacetate/petroleum ether) provided4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(77 mg, 20%). ESI-MS m/z calc. 345.05, found 346.0 (M+1)+; 344.0 (M−1)−;retention time (Method F): 0.76 minutes (1.5 minute run).

Step 3: 2-(Difluoromethoxy)-4-fluoro-phenol

To sodium iodide (2.24 g, 15.0 mmol) in acetonitrile (10 mL) under a N₂atmosphere was added TMSCl (1.63 g, 1.90 mL, 15.0 mmol) and the mixturewas stirred 20 minutes. 2-(Difluoromethoxy)-4-fluoro-1-methoxy-benzene(575 mg, 2.99 mmol) was added and the mixture was heated at 80° C. for 6hours, then the heat was reduced to 70° C. for 16 hours. The reactionwas concentrated in vacuo and the residue was partitioned betweendichloromethane and 1 M aqueous sodium thiosulfate. The organic layerwas separated and the aqueous layer was further extracted withdichloromethane. The combined organics were dried over MgSO₄,concentrated and purified by silica gel chromatography (0-30% ethylacetate/hexanes) to provide 2-(difluoromethoxy)-4-fluoro-phenol (325 mg,61%) as a pale yellow oil. ESI-MS retention time (Method A): 0.45minutes (1.2 minute run). ¹H NMR (400 MHz, CDCl₃) δ 7.04-6.79 (m, 3H),6.53 (t, J=73.0 Hz, 1H), 5.22 (s, 1H) ppm.

Step 4:4-[[6-[2-(Difluoromethoxy)-4-fluoro-phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(208)

In a microwave vial were combined4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(40 mg, 0.12 mmol), 2-(difluoromethoxy)-4-fluoro-phenol (52 mg, 0.29mmol) and Cs₂CO₃ (57 mg, 0.18 mmol) in DMF (1 mL). The resultingsuspension was heated to 90° C. for 30 minutes using microwaveirradiation. The reaction mixture was cooled, filtered and diluted withDMSO. Two sequential HPLC purifications (initial purification usingacetonitrile/0.1% ammonium hydroxide gradient followed by finalpurification using acetonitrile/0.05% TFA gradient) provided4-[[6-[2-(difluoromethoxy)-4-fluoro-phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamidetrifluoroacetate (11 mg, 15%) as a white solid. ESI-MS m/z calc. 503.07,found 504.0 (M+1)+; 502.0 (M−1)−; retention time (Method E): 3.07minutes (4.45 minute run). ¹H NMR (500 MHz, DMSO-d6) δ 11.47 (s, 1H),8.57 (d, J=5.5 Hz, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.12 (d, J=2.7 Hz, 1H),7.90-7.81 (m, 2H), 7.68 (d, J=2.6 Hz, 1H), 7.50-7.39 (m, 2H), 7.38-7.06(m, 2H), 6.77 (d, J=8.9 Hz, 1H) ppm.

Example 134N-(3-Carbamoyl-4-fluoro-phenyl)-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(68)

Step 1:5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicAcid

2-Methoxy-4-(trifluoromethoxy)phenol (prepared as described in Example2, 1.01 g, 4.48 mmol), 5-bromo-2-(trifluoromethyl)pyridine-4-carboxylicacid (1.00 g, 3.70 mmol), Cs₂CO₃ (2.60 g, 7.98 mmol) and toluene (20 mL)were combined and heated at 100° C. After 10 minutes, copper (I) iodide(140 mg, 0.735 mmol) was added and the reaction was stirred at 100° C.for 2.5 hours. The reaction mixture was cooled to room temperature andpartitioned between ethyl acetate and 1 M HCl. The organic phase wasseparated and washed with water and brine, dried over Na₂SO₄, filteredand concentrated. The residue was triturated in dichloromethane andfiltered to provide5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (620 mg, 42%) as a white solid. ESI-MS m/z calc. 397.04, found398.0 (M+1)+; retention time (Method A): minutes 0.71 (1.2 minute run).

Step 2:N-(3-Carbamoyl-4-fluoro-phenyl)-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(68)

5-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (150 mg, 0.378 mmol) and HATU (144 mg, 0.379 mmol) were combined inDMF (2 mL) and DIEA (0.165 mL, 0.947 mmol) and stirred for 10 minutes,followed by the addition of 5-amino-2-fluoro-benzamide (116 mg, 0.753mmol). The reaction was stirred for 1 hour, then diluted withdichloromethane and washed with water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. HPLC purification(10-99% acetonitrile/5 mM HCl) providedN-(3-carbamoyl-4-fluoro-phenyl)-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(21.8 mg, 10%). ESI-MS m/z calc. 533.08, found 534.1 (M+1)+; retentiontime (Method B): 1.84 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.83 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.99-7.95 (m, 1H), 7.78(ddd, J=9.0, 4.4, 2.8 Hz, 1H), 7.70 (br s, 2H), 7.38 (d, J=8.8 Hz, 1H),7.29 (dd, J=10.1, 9.0 Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.02 (ddd, J=8.8,2.7, 1.2 Hz, 1H), 3.78 (s, 3H) ppm.

Example 135N-(2-Carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxamide(119)

Step 1: Methyl 6-bromo-4-chloro-pyridine-3-carboxylate

A 5000-mL 3-neck round bottom flask was fitted with a mechanicalstirrer, a cooling bath, an addition funnel, a J-Kem temperature probeand a N₂ inlet/outlet. The vessel was charged under a N₂ atmosphere with6-bromo-4-chloro-pyridine-3-carboxylic acid (250 g, 1.06 mol) and1-methyl-pyrrolidin-2-one (1.250 L) which provided a clear pale ambersolution (internal temperature 19° C.). Potassium carbonate (146.1 g,1.057 mol) was added to the stirring solution as a solid in one portionand the mixture was stirred for 30 minutes. Neat dimethyl sulfate (133.3g, 100.0 mL, 1.057 mol) was added dropwise over 30 minutes resulting inan exotherm to 26° C. The mixture was stirred at room temperature for 2hours and then cooled to 0° C. Ice cold water (3000 mL) was addeddropwise to the reaction mixture over 1 hour resulting in a thicksuspension. The cooling bath was removed and the suspension was stirredfor 1 hour. The solid was collected by vacuum filtration and the filtercake was washed with water (3×500 mL) and air dried for 1 hour. Thematerial was further dried in a vacuum oven at 45° C. for 24 hours toprovide methyl 6-bromo-4-chloro-pyridine-3-carboxylate (255 g, 96%) asan off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=0.4 Hz, 1H),8.13 (d, J=0.5 Hz, 1H), 3.90 (s, 3H) ppm.

Step 2: Methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

A 5000-mL 3-neck round bottom flask was fitted with a mechanicalstirrer, a cooling bath, a J-Kem temperature probe and a N₂inlet/outlet. The vessel was charged under a N₂ atmosphere with methyl6-bromo-4-chloro-pyridine-3-carboxylate (175 g, 698.7 mmol) and DMF(1.750 L) (10 ml/g) which provided a clear pale yellow solution. Thestirring solution was cooled to 0° C. then charged with2-methoxy-4-(trifluoromethoxy)phenol (prepared as described in Example2, 145.4 g, 698.6 mmol) added as a solid in one portion followed bycesium carbonate (341.5 g, 1.048 mol) added as a solid in one portion.The reaction mixture was stirred in the ice bath for 10 minutes thenallowed to warm to room temperature and stirred for 2 hours. Theresulting suspension was then added slowly to 4 L of stirring cold waterand the resulting slurry was continued to stir at room temperature for30 minutes. The material was collected by vacuum filtration and thefilter cake was washed with water (3×250 mL) and air dried for 16 hoursto provide an off-white solid (160 g). The material was suspended inheptane (1500 mL) and heated to reflux. The solution was clarified byvacuum filtration through a glass frit Buchner funnel. The filtrate wasthen heated to reflux and the resulting clear solution was allowed toslowly cool to room temperature during which time a solid formed. Thematerial was collected by vacuum filtration and the filter cake waswashed with cold heptane (2×50 mL). Vacuum was pulled in the funnel for30 minutes and the material further dried in the vacuum oven at 45° C.for 12 hours to provide methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(275 g, 93%) as of a white solid. ESI-MS m/z calc. 420.97, found 424.0(M+1)+; retention time (Method B): 1.84 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.29 (d,J=2.7 Hz, 1H), 7.06 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.80 (s, 1H), 3.86(s, 3H), 3.80 (s, 3H) ppm.

Step 3: Methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)vinyl]pyridine-3-carboxylate

A vial was charged with methyl6-bromo-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(800 mg, 1.90 mmol),4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (550mg, 2.48 mmol), Pd(dppf)Cl₂.DCM (155 mg, 0.190 mmol), K₂CO₃ (2 mL of 2 Min water, 4 mmol) and acetonitrile (8 mL). The vial was flushed withargon, sealed and heated at 80° C. for 90 minutes. The reaction mixturewas cooled to room temperature and partitioned between water and ethylacetate. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel column chromatography (0-20% ethylacetate/hexanes) provided methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)vinyl]pyridine-3-carboxylate(340 mg, 41%). ESI-MS m/z calc. 437.06, found 438.2 (M+1)+; retentiontime (Method B): 2.07 minutes (3 minute run).

Step 4: Methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxylate

Preparation of a solution of diazomethane in ethyl ether: To1-methyl-1-nitroso-urea (1.00 g, 9.70 mmol) was added a biphasic mixtureof 40% aqueous KOH (2.0 mL of 40% w/v, 14.3 mmol) and diethyl ether (2mL) cooled in an ice-bath. The mixture was stirred in the ice-bath for10 minutes (turns yellow), and then cooled to −78° C. The ether layerwas decanted from the frozen aqueous layer and the yellow solution wasused directly in the next step.

The diazomethane solution was added dropwise to a solution of methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)vinyl]pyridine-3-carboxylate(470 mg, 1.08 mmol) in diethyl ether (7 mL) at 0° C. The yellow color ofthe diazomethane disappeared upon addition. The reaction was stirred at0° C. for 5 minutes. Acetic acid (3 mL) was added to quench the excessdiazomethane until the reaction mixture was colorless and gas evolutionhad ceased. The mixture was diluted with ethyl acetate (10 mL), washedwith saturated aqueous NaHCO₃ (20 mL), brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuo to provide the intermediatemethyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[5-(trifluoromethyl)-3,4-dihydropyrazol-5-yl]pyridine-3-carboxylate(500 mg, 97%) as a yellow oil. ESI-MS m/z calc. 479.09, found 480.2(M+1)+; retention time (Method B): 2.04 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.41-7.29 (m, 2H), 7.08 (ddq, J=8.8,2.5, 1.2 Hz, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 1.46-1.37(m, 4H) ppm.

The4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[5-(trifluoromethyl)-3,4-dihydropyrazol-5-yl]pyridine-3-carboxylatewas dissolved in p-xylene (7 mL) and heated at reflux (125° C.) open toair for 2 hours. The solvent was evaporated and the crude material waspurified by silica gel column chromatography (0-10% ethylacetate/hexanes) to obtain methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxylate(135 mg, 56%). ESI-MS m/z calc. 451.08, found 452.3 (M+1)+; retentiontime (Method B): 1.9 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ8.84 (s, 1H), 7.41-7.29 (m, 2H), 7.08 (ddq, J=8.8, 2.5, 1.2 Hz, 1H),6.64 (s, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 1.46-1.37 (m, 4H) ppm.

Step 5:4-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxylicAcid

To a solution of methyl4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxylate(128 mg, 0.284 mmol) in methanol (1.2 mL) was added NaOH (270 mg, 6.75mmol) in water (1.2 mL). The reaction mixture was stirred at roomtemperature for 1 hour. The solvent was evaporated and the reactionmixture was quenched with 6 M HCl. The aqueous layer was extracted withethyl acetate, dried over MgSO₄, filtered and concentrated in vacuo toprovide4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxylicacid (120 mg, 97%). ESI-MS m/z calc. 437.06, found 438.5 (M+1)+;retention time (Method B): 1.88 minutes (3 minute run).

Step 6:N-(2-Carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxamide(119)

A vial was charged with4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxylicacid (19 mg, 0.043 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Preparation 1, 15 mg, 0.04567 mmol),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (2 mg, 0.006 mmol) in2-propanol (0.5 mL) and heated at 83° C. under an air atmosphere for 20hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (0-60% ethyl acetate/hexanes) followed by HPLCpurification (10-99% acetonitrile/5 mM HCl). The desired fractions werequenched with saturated NaHCO₃ and extracted with dichloromethane, driedover MgSO₄ and concentrated in vacuo to obtainN-(2-carbamoyl-4-pyridyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxamide(8 mg, 33%). ESI-MS m/z calc. 556.11, found 557.2 (M+1)+; retention time(Method B): 1.86 minutes (3 minute run). ¹H NMR (400 MHz, DMF-d7) δ11.46 (s, 1H), 9.15 (s, 1H), 8.97 (d, J=5.5 Hz, 1H), 8.75 (d, J=2.2 Hz,1H), 8.52 (s, 1H), 8.32 (dd, J=5.5, 2.2 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H),7.91 (d, J=8.8 Hz, 1H), 7.72 (d, J=2.7 Hz, 1H), 7.59-7.43 (m, 1H), 7.13(s, 1H), 4.20 (s, 3H), 1.85 (d, J=4.3 Hz, 4H) ppm.

Example 136N-(3-Carbamoyl-4-fluoro-phenyl)-2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(55)

Step 1: 2,3-Difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicAcid

6-Bromo-2,3-difluoro-benzoic acid (1.00 g, 4.22 mmol),2-methoxy-4-(trifluoromethoxy)phenol (prepared as described in Example2, 1.02 g, 4.91 mmol) and Cs₂CO₃ (2.76 g, 8.46 mmol) in toluene (10 mL)were combined in a pressure vessel and the mixture was bubbled with N₂for 3 minutes. Copper (I) iodide (168 mg, 0.881 mmol) was added and thereaction was stirred at 100° C. for 1.5 hours in the sealed vessel. Thereaction mixture was cooled then partitioned between ethyl acetate andwater. The aqueous layer was acidified to pH-1 and extracted with ethylacetate (3×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo to yield2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (336mg, 22%). ESI-MS m/z calc. 364.04, found 365.1 (M+1)+; retention time(Method C): 2.23 minutes (5 minute run).

Step 2: 2,3-Difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride

To a solution of2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (326mg, 0.895 mmol) and DMF (10 μL, 0.13 mmol) in dichloromethane (3 mL) at0° C. was added oxalyl chloride (500 μL, 5.73 mmol) dropwise. The icebath was removed and the reaction was stirred under a N₂ atmosphere for35 minutes. Conversion was monitored by UPLC via test for piperidineadduct formation. The solvent was evaporated in vacuo to afford2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl chloridewhich was used directly for the next step.

Step 3:N-(3-Carbamoyl-4-fluoro-phenyl)-2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(55)

To a solution of 5-amino-2-fluoro-benzamide (60 mg, 0.39 mmol) and DIEA(0.204 mL, 1.18 mmol) in dichloromethane (1 mL) at 0° C. was added asolution of2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl chloride(150 mg, 0.392 mmol) in dichloromethane (1 mL) dropwise. The reactionwas allowed to warm to room temperature and stirred for 2 hours. Thesolvent was evaporated under a stream of N₂ gas. The crude product wasdissolved in DMSO, filtered and purified by HPLC (1-99% acetonitrile/5mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(22.3 mg, 11%). ESI-MS m/z calc. 500.08, found 501.1 (M+1)+; retentiontime (Method C): 2.22 minutes (5 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.94 (s, 1H), 7.98 (dd, J=6.4, 2.8 Hz, 1H), 7.82-7.64 (m, 3H),7.54-7.41 (m, 1H), 7.28 (dd, J=10.0, 8.9 Hz, 1H), 7.23-7.17 (m, 2H),7.09-6.81 (m, 1H), 6.81-6.43 (m, 1H), 3.77 (s, 3H) ppm.

Example 1374-[[4-Cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(125)

Step 1:4-Bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde

A vial charged with 2-methoxy-4-(trifluoromethoxy)phenol (prepared asdescribed in Example 2, 768 mg, 3.69 mmol),4-bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde (1.00 g, 3.69 mmol),Cs₂CO₃ (3.01 g, 9.23 mmol) and DMF (3 mL) was heated at 80° C. for 2hours. The reaction mixture was diluted with water and the resultingprecipitate was filtered and washed with water. The solid was dissolvedin dichloromethane, dried over MgSO₄, filtered and concentrated invacuo. The crude material was purified by silica gel chromatography(0-5% ethyl acetate/hexanes) to provide4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde(725 mg, 43%). ESI-MS m/z calc. 457.95, found 461.1 (M+1)+; retentiontime (Method B): 2.26 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.43 (s, 1H), 8.12 (s, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.31 (d, J=2.7Hz, 1H), 7.12 (s, 1H), 7.09 (ddq, J=8.8, 2.4, 1.2 Hz, 1H), 3.81 (s, 3H)ppm.

Step 2:4-Cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde

To a round bottom flask equipped with a stir bar were added4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde(725 mg, 1.58 mmol) and bis(tri-tert-butylphosphine)palladium(0) (245mg, 0.479 mmol). The flask was sealed with a septum, placed under a N₂atmosphere and THF (7.5 mL) added. The reaction mixture was cooled to 0°C. and a solution of bromo(cyclopropyl)zinc (6.4 mL of 0.5 M in THF, 3.2mmol) was added dropwise to the reaction mixture. After 30 minutes thereaction was quenched with saturated aqueous NH₄Cl solution andextracted with ethyl acetate. The organic layer was separated and driedover Na₂SO₄, filtered and concentrated in vacuo. Silica gel columnchromatography (0-5% ethyl acetate/hexanes) provided4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde(390 mg, 59%) as an off-white solid. ESI-MS m/z calc. 420.07, found421.2 (M+1)+; retention time (Method B): 2.3 minutes (3 minute run). ¹HNMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.03 (s, 1H), 7.36 (d, J=8.8 Hz,1H), 7.28 (d, J=2.8 Hz, 1H), 7.05 (ddq, J=8.8, 2.4, 1.1 Hz, 1H), 6.27(s, 1H), 3.79 (s, 3H), 2.18-2.06 (m, 1H), 1.21-0.98 (m, 2H), 0.64-0.35(m, 2H) ppm.

Step 3:4-Cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicAcid

A solution of4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde(390 mg, 0.928 mmol) in tert-butyl alcohol (4 mL), water (2.5 mL) andacetonitrile (2.5 mL) was treated with sodium dihydrogen phosphate (144mg, 1.20 mmol) added in one portion followed by 2-methyl-2-butene (0.50mL, 4.73 mmol). Sodium chlorite (100 mg, 1.11 mmol) was then addedportion wise (exotherm to 33° C., internal temperature) and the reactionmixture was stirred at room temperature for 16 hours. The reactionmixture was adjusted to pH-2 by the addition of 1 M HCl solution. Theorganic phase was separated and the aqueous layer was extracted withethyl acetate (3×10 mL). The combined organics were dried over MgSO₄,filtered and concentrated in vacuo. The resulting solid was furtherdried under high vacuum for 24 hours to provide4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid (320 mg, 79%) as an off-white solid. ESI-MS m/z calc. 436.07, found437.3 (M+1)+; retention time (Method A): 0.81 minutes (1.2 minute run).

Step 4:4-[[4-Cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(125)

A vial was charged with4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid (50 mg, 0.12 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in preparation 1, 37 mg, 0.11 mmol),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (3 mg, 0.008 mmol) in2-propanol (0.7 mL) and heated at 83° C. under an atmosphere of air for20 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. Purification by silica gel chromatography (0-60%ethyl acetate/hexanes) was followed by HPLC purification (10-99%acetonitrile/5 mM HCl). The product HPLC fractions were basified withsaturated NaHCO₃, extracted with dichloromethane, dried over MgSO₄ andconcentrated in vacuo to provide4-[[4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(8 mg, 13%). ESI-MS m/z calc. 555.12, found 556.3 (M+1)+; retention time(Method B): 2.12 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ10.87 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.28 (d, J=2.1 Hz, 1H), 8.07 (d,J=2.9 Hz, 1H), 7.95 (s, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.62 (d,J=2.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 6.99(ddd, J=8.7, 2.8, 1.3 Hz, 1H), 6.41 (s, 1H), 3.75 (s, 3H), 2.14 (s, 1H),1.11-0.99 (m, 2H), 0.59 (dd, J=6.7, 4.7 Hz, 2H) ppm.

Example 138N-(3-Carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)benzamide(40)

Step 1:N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(trifluoromethyl)benzamide

To a solution of 2-fluoro-6-(trifluoromethyl)benzoyl chloride (1.00 mL,6.49 mmol) and DIEA (3.28 mL, 18.8 mmol) in dichloromethane (15 mL) at0° C. was added a solution of 5-amino-2-fluoro-benzamide (1.00 g, 6.49mmol) in dichloromethane (10 mL) dropwise. The reaction mixture wasallowed to warm to room temperature, stirred for 20 minutes thenconcentrated in vacuo. Silica gel chromatography (0-50% ethylacetate/hexanes) providedN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(trifluoromethyl)benzamide(1.3 g, 58%). ESI-MS m/z calc. 344.05, found 345.2 (M+1)+; retentiontime (Method A): 0.46 minutes (1.2 minute run).

Step 2:N-(3-Carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)benzamide(40)

N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(trifluoromethyl)benzamide(50 mg, 0.15 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (prepared asdescribed in Example 2, 60 mg, 0.29 mmol) and Cs₂CO₃ (95 mg, 0.29 mmol)were combined in DMF (1 mL) and heated at 100° C. for 1 hour. Thereaction was cooled to room temperature, diluted with DMSO (0.5 mL) andpurified by HPLC (1-70% acetonitrile/5 mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)benzamide(14.8 mg, 18%). ESI-MS m/z calc. 532.08, found 533.2 (M+1)+; retentiontime (Method B): 1.66 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.84 (s, 1H), 7.97 (dd, J=6.4, 2.8 Hz, 1H), 7.77-7.72 (m, 2H), 7.69(s, 1H), 7.60 (td, J=8.0, 0.9 Hz, 1H), 7.57-7.53 (m, 1H), 7.31-7.21 (m,3H), 7.06-6.98 (m, 2H), 3.80 (s, 3H) ppm.

Example 139N-(3-Carbamoyl-4-fluoro-phenyl)-6-cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(88)

Step 1: Methyl6-bromo-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

Methyl 6-bromo-4-chloro-pyridine-3-carboxylate (prepared as described inExample 135, step 1, 757 mg, 3.02 mmol) was dissolved in anhydrous DMF(7.6 mL) under a N₂ atmosphere and cooled to 0° C.2-(Trideuteriomethoxy)-4-(trifluoromethoxy)phenol (prepared as describedin Example 1, step 1, 0.638 g, 3.02 mmol) was added in one portionfollowed by Cs₂CO₃ (2.95 g, 9.05 mmol). The reaction mixture was stirredfor 10 minutes at 0° C. then the cooling bath was removed and thereaction mixture was stirred for an additional 2 hours at roomtemperature. The reaction mixture was partitioned between ethyl acetateand brine and the layers separated. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-10% ethyl acetate/hexanes) provided methyl6-bromo-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(1 g, 78%). ESI-MS m/z calc. 423.99, found 425.1 (M+1)+; retention time(Method A): 0.75 minutes (1.2 minute run).

Step 2: Methyl6-cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

A flask was charged with a stir bar, methyl6-bromo-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(1.00 g, 2.35 mmol) and bis(tri-t-butylphosphine)palladium(0) (144 mg,0.282 mmol). The flask was sealed with a septum, placed under a N₂atmosphere, and anhydrous THF (2.4 mL) was added. The resulting slurrywas cooled to 0° C. and treated dropwise with a solution ofbromo(cyclopropyl)zinc (5.6 mL of 0.5 M in THF, 2.8 mmol) over 30minutes. The reaction was stirred for 30 minutes then quenched withsaturated aqueous NH₄Cl solution and extracted with ethyl acetate. Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.Silica gel chromatography (0-10% ethyl acetate/hexanes) provided methyl6-cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(710 mg, 78%). ESI-MS m/z calc. 386.11, found 387.2 (M+1)+; retentiontime (Method A): 0.61 minutes (1.2 minute run).

Step 3:6-Cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicAcid

Methyl6-cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(710 mg, 1.84 mmol) was dissolved in methanol (10 mL) and treated with asolution of NaOH (735 mg, 18.4 mmol) in water (4 mL). The reactionmixture was stirred at room temperature for 1 hour. The solvents wereremoved under reduced pressure and the resulting white slurry wasdissolved in water (100 mL), cooled to 0° C. and treated dropwise with 6M HCl until pH2 was reached. The resulting precipitate was collected byvacuum filtration and the filter cake was further washed with water. Thefilter cake was then dried in a desiccator filled with Drierite® underhigh vacuum for 16 hours to obtain6-cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (630 mg, 92%) as a white solid. ESI-MS m/z calc. 372.10, found373.2 (M+1)+; retention time (Method A): 0.5 minutes (1.2 minute run).

Step 4:N-(3-Carbamoyl-4-fluoro-phenyl)-6-cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(88)

A mixture of6-cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (100 mg, 0.269 mmol), HATU (103 mg, 0.270 mmol) and4-methylmorpholine (0.06 mL, 0.55 mmol) in DMF (0.5 mL) was stirred atroom temperature for 5 minutes and then 5-amino-2-fluoro-benzamide (41mg, 0.27 mmol) was added in one portion. The reaction was stirred for 30minutes, then diluted to a total volume of 1 mL with DMF, filtered andpurified by HPLC (30-99% acetonitrile/5 mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-6-cyclopropyl-4-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(72 mg, 52%). ESI-MS m/z calc. 508.15, found 509.2 (M+1)+; retentiontime (Method B): 1.35 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.61 (s, 1H), 8.67 (s, 1H), 8.00 (dd, J=6.4, 2.8 Hz, 1H), 7.83 (ddd,J=8.9, 4.4, 2.8 Hz, 1H), 7.70 (d, J=10.7 Hz, 2H), 7.49 (d, J=8.8 Hz,1H), 7.32-7.24 (m, 2H), 7.08 (ddq, J=8.9, 2.4, 1.2 Hz, 1H), 6.69 (s,1H), 2.18 (dt, J=7.7, 4.6 Hz, 1H), 1.09-0.97 (m, 4H) ppm.

Example 140N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(126)

Step 1:6-Bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-3-(trifluoromethyl)benzamide

6-Bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.00 g, 6.97 mmol) andHATU (2.65 g, 6.97 mmol) were combined in DMF (20 mL) and treated withDIEA (3.6 mL, 21 mmol). The mixture was stirred for 5 minutes thentreated with 5-amino-2-fluoro-benzamide (1.08 g, 6.97 mmol). Thereaction mixture was stirred for 1 hour then diluted with ethyl acetateand washed with 50% saturated NaHCO₃ solution, water, and brine. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. The resulting solid was triturated with dichloromethane, andfiltered to provide crop 1 of the desired product (1.91 g). The motherliquor was concentrated and purified by silica gel chromatography(0-100% ethyl acetate/hexanes) to provide an additional 470 mg ofproduct. Total yield of6-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-3-(trifluoromethyl)benzamide(2.38 g, 81%). ESI-MS m/z calc. 421.96, found 425.0 (M+1)+; retentiontime (Method B): 1.34 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.08 (s, 1H), 7.98 (dd, J=6.3, 2.8 Hz, 1H), 7.92-7.83 (m, 2H),7.80-7.73 (m, 2H), 7.72 (br s, 1H), 7.32 (dd, J=10.1, 8.9 Hz, 1H) ppm.

Step 2: 3-Methoxy-4-(trifluoromethoxy)phenol

To a solution of [3-methoxy-4-(trifluoromethoxy)phenyl]boronic acid(1.00 g, 4.24 mmol) in ethanol (12 mL) was added hydrogen peroxide (1.37g of 35% w/v, 12.7 mmol) and the reaction was stirred at roomtemperature for 16 hours. The reaction mixture was partitioned betweenwater (15 mL) and ethyl acetate (30 mL). The organic layer was washedwith saturated aqueous NaHCO₃ solution, dried over Na₂SO₄, andconcentrated in vacuo to provide 3-methoxy-4-(trifluoromethoxy)phenol(350 mg, 40%). ESI-MS m/z calc. 208.03, found 209.1 (M+1)+; retentiontime (Method B): 1.27 minutes (3 minute run).

Step 3:N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(126)

To a microwave vial was added6-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-3-(trifluoromethyl)benzamide(200 mg, 0.473 mmol), Cs₂CO₃ (308 mg, 0.945 mmol),3-methoxy-4-(trifluoromethoxy)phenol (98 mg, 0.47 mmol) and toluene (2mL, degassed with N₂ bubbling). The mixture was bubbled with N₂ gas,then copper (I) iodide (18 mg, 0.095 mmol) was added and the reactionwas stirred at 100° C. for 20 minutes. The reaction was diluted withethyl acetate and water, and the layers separated. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was triturated in hexane and filtered to obtainN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(50 mg, 19%). ESI-MS m/z calc. 550.07, found 551.2 (M+1)+; retentiontime (Method B): 1.9 minutes (3 minute run).

Example 1415-[[4-(Difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(174)

Step 1: Methyl 4-(difluoromethoxy)-2,6-difluoro-benzoate

To a suspension of 4-(difluoromethoxy)-2,6-difluoro-benzoic acid (900mg, 4.02 mmol) in dichloromethane (10 mL) and methanol (3.5 mL, 86 mmol)at 0° C. under N₂ atmosphere was added a solution ofdiazomethyl(trimethyl)silane (3.4 mL of 2 M in hexanes, 6.8 mmol)dropwise (persistent yellow color). The mixture was stirred 10 minutesthen several drops of acetic acid were added to quench excess reagent(until colorless). The reaction mixture was concentrated in vacuo,dissolved in dichloromethane and washed with saturated aqueous NaHCO₃,dried over MgSO₄ and concentrated. Silica gel chromatography (0-10%ethyl acetate/dichloromethane) provided methyl4-(difluoromethoxy)-2,6-difluoro-benzoate (746 mg, 74%). ¹H NMR (400MHz, DMSO-d6) δ 7.43 (t, J=72.6 Hz, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.21(d, J=1.9 Hz, 1H), 3.88 (s, 3H) ppm.

Step 2: Methyl4-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate

A vial charged with 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol(prepared as described in Example 1, step 1, 630 mg, 2.98 mmol), methyl4-(difluoromethoxy)-2,6-difluoro-benzoate (750 mg, 2.99 mmol), Cs₂CO₃(2.10 g, 6.45 mmol) in DMF (8 mL) was heated at 80° C. for 90 minutes.The reaction mixture was cooled to room temperature and partitionedbetween water and ethyl acetate. The organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-5% ethyl acetate/hexanes) provided methyl4-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(780 mg, 61%). ESI-MS m/z calc. 429.07, found 430.2 (M+1)+; retentiontime (Method B): 1.95 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 7.50-7.10 (m, 3H), 7.04-6.97 (m, 2H), 6.34-6.30 (m, 1H), 3.82 (s, 3H)ppm.

Step 3:4-(Difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicAcid

To a solution of methyl4-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(575 mg, 1.34 mmol) in methanol (1 mL) was added NaOH (800 mg, 20.0mmol) and water (1 mL). The reaction mixture was stirred at roomtemperature for 15 hours. The solvent was evaporated and the reactionmixture was quenched with 6 M HCl. The aqueous layer was extracted byethyl acetate, dried over MgSO₄, filtered and concentrated in vacuo toprovide4-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (347 mg, 62%). ESI-MS m/z calc. 415.05, found 416.2 (M+1)+;retention time (Method B): 1.68 minutes (3 minute run).

Step 4:4-(Difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoylchloride

To a solution of4-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (200 mg, 0.482 mmol) and DMF (35 μL, 0.45 mmol) in dichloromethane(3 mL) at 0° C. was added oxalyl chloride (0.045 mL, 0.52 mmol)dropwise. The mixture was stirred at room temperature for 90 minutes andconversion was monitored by UPLC via test for morpholine adductformation. The acid chloride was used as a solution for the next step.

Step 5:5-[[4-(Difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(174)

To a flask charged with 5-aminopyridine-2-carboxamide (48 mg, 0.35 mmol)and DIEA (0.150 mL, 0.861 mmol) in dichloromethane (1 mL) was added asolution of4-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoylchloride (100 mg, 0.231 mmol) in dichloromethane (1.5 mL) at 0° C.dropwise under an N₂ atmosphere. The reaction mixture was stirred for 16hours at room temperature then diluted with water and extracted withdichloromethane. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-60% ethylacetate/hexanes) provided5-[[4-(difluoromethoxy)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(22 mg, 18%). ESI-MS m/z calc. 534.10, found 535.2 (M+1)+; retentiontime (Method B): 1.67 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.18 (s, 1H), 8.85 (dd, J=2.5, 0.7 Hz, 1H), 8.25 (dd, J=8.6, 2.5 Hz,1H), 8.08-7.97 (m, 2H), 7.60-6.93 (m, 6H), 6.37 (t, J=1.7 Hz, 1H) ppm.

Example 142N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(141)

N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(26, prepared as described in Example 140, 30 mg, 0.055 mmol) wasdissolved in dichloromethane (0.6 mL) and cooled to −78° C. (dryice/acetone bath). The solution was treated dropwise with a solution ofBBr₃ (0.27 mL of 1.0 M in dichloromethane, 0.27 mmol) and stirred for 10minutes. The reaction mixture was removed from the dry ice bath andallowed to come to room temperature and stirred for 20 minutes. Thereaction mixture was diluted with dichloromethane and washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentratedin vacuo. Silica gel chromatography (0-25% ethylacetate/dichloromethane) providedN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(17 mg, 57%) as a pale yellow solid. ESI-MS m/z calc. 536.06, found537.2 (M+1)+; retention time (Method B): 1.6 minutes (3 minute run). ¹HNMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.62 (s, 1H), 7.96 (dd, J=6.4,2.8 Hz, 1H), 7.86 (t, J=8.7 Hz, 1H), 7.76 (ddd, J=8.9, 4.4, 2.9 Hz, 1H),7.70 (d, J=17.4 Hz, 2H), 7.36 (dq, J=8.8, 1.2 Hz, 1H), 7.29 (dd, J=10.1,8.9 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.80 (d, J=2.9 Hz, 1H), 6.68 (dd,J=8.9, 2.8 Hz, 1H) ppm. ¹⁹F NMR (376 MHz, DMSO-d6) δ −57.33, −59.25,−59.28, −117.44, −118.46 ppm.

Example 1434-[[2-[2-(Trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(147)

Step 1: 2-Fluoro-4-(trifluoromethoxy)benzoyl chloride

To a solution of 2-fluoro-4-(trifluoromethoxy)benzoic acid (13.86 g,109.2 mmol) and DMF (161 μL, 2.08 mmol) in dichloromethane (51 mL) at 0°C. was added oxalyl chloride (9.53 mL, 109 mmol) dropwise. The mixturewas stirred at room temperature for 5 hours under N₂ atmosphere withconversion to product monitored by UPLC via test for[2-fluoro-4-(trifluoromethoxy)phenyl]-morpholino-methanone piperidineadduct formation. The solvent was evaporated in vacuo to afford2-fluoro-4-(trifluoromethoxy)benzoyl chloride (3.5 g, 63%).

Step 2:4-[[2-Fluoro-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide

To a solution of 4-aminopyridine-2-carboxamide (2.90 g, 21.2 mmol) andDIEA (7.19 g, 55.7 mmol) in NMP (27 mL) at 0° C. was added dropwise asolution of 2-fluoro-4-(trifluoromethoxy)benzoyl chloride (5.40 g, 22.3mmol) in dichloromethane (27 mL). The reaction mixture was removed fromthe ice bath and stirred at room temperature for 16 hours. The reactionmixture was partitioned between water and ethyl acetate. The layers wereseparated and the aqueous layer was extracted with additional ethylacetate. The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo. The crude material was triturated with amixture of hexanes/dichloromethane and the solid was collected by vacuumfiltration to obtain4-[[2-fluoro-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(650 mg, 9%). ESI-MS m/z calc. 343.05, found 344.1 (M+1)+; retentiontime (Method B): 1.65 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.09 (s, 1H), 8.56 (d, J=5.6 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.11(d, J=2.7 Hz, 1H), 7.95-7.80 (m, 2H), 7.74-7.54 (m, 2H), 7.50-7.32 (m,1H) ppm.

Step 3:4-[[2-[2-(Trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(147)

A mixture of4-[[2-fluoro-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(75 mg, 0.22 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol(prepared as described in Example 1 step 1, 46 mg, 0.22 mmol) and K₂CO₃(91 mg, 0.66 mmol) in DMF (0.75 mL) was heated at 100° C. for 2 hours.The reaction mixture was cooled to room temperature, filtered anddiluted with DMSO (1 mL). HPLC purification (10-99% acetonitrile/5 mMHCl) provided4-[[2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(46.5 mg, 39%) as a white solid. ESI-MS m/z calc. 534.10, found 535.5(M+1)+; retention time (Method B): 1.83 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.52 (d, J=5.4 Hz, 1H), 8.32 (d,J=2.0 Hz, 1H), 8.11 (d, J=2.8 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H),7.81 (d, J=8.5 Hz, 1H), 7.63 (d, J=2.7 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H),7.24 (ddd, J=8.5, 2.3, 1.2 Hz, 1H), 7.18 (dd, J=2.8, 0.7 Hz, 1H), 7.02(ddq, J=8.8, 2.4, 1.2 Hz, 1H), 6.69 (dd, J=2.2, 0.9 Hz, 1H) ppm. ¹⁹F NMR(376 MHz, DMSO-d6) δ −56.8, −56.93, ppm.

Example 1444-[[6-[4-(Difluoromethoxy)-2-fluoro-phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(136)

To a microwave vial was added4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(prepared as described in Example 136, step 2, 50 mg, 0.12 mmol), Cs₂CO₃(80 mg, 0.25 mmol), 4-(difluoromethoxy)-2-fluoro-phenol (22 mg, 0.12mmol) and toluene (0.5 mL, degassed by N₂ bubbling). The mixture wasbubbled with N₂ gas, treated with copper (I) iodide (13 mg, 0.07 mmol)and stirred at 100° C. for 20 minutes. The reaction was partitionedbetween ethyl acetate and water and the layers separated. The organiclayer was concentrated in vacuo. The residue was dissolved in DMSO (2mL) and purified by HPLC (10-99% acetonitrile/5 mM HCl) to provide4-[[6-[4-(difluoromethoxy)-2-fluoro-phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(35 mg, 56%). ESI-MS m/z calc. 503.07, found 504.3 (M+1)+; retentiontime (Method B): 1.61 minutes (3 minute run).

Example 145N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-fluoro-2-(2-methylpyrazol-3-yl)phenoxy]-3-(trifluoromethyl)benzamide(135)

To a microwave vial was added6-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-3-(trifluoromethyl)benzamide(75 mg, 0.18 mmol, prepared as described in Example 140, step 1), Cs₂CO₃(116 mg, 0.36 mmol), 4-fluoro-2-(2-methylpyrazol-3-yl)phenol (34 mg,0.18 mmol) and toluene (0.34 mL, degassed with N₂ bubbling). The mixturewas bubbled with N₂ gas then treated with copper (I) iodide (18 mg, 0.10mmol) and stirred at 100° C. for 20 minutes. The reaction waspartitioned between ethyl acetate and water, and the layers separated.The organic layer was concentrated in vacuo. The residue was dissolvedDMSO (2 mL) and purified by HPLC (10-99% acetonitrile/5 mM HCl) toprovideN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-fluoro-2-(2-methylpyrazol-3-yl)phenoxy]-3-(trifluoromethyl)benzamide(10.3 mg, 11%). ESI-MS m/z calc. 534.11, found 535.2 (M+1)+; retentiontime (Method B): 1.52 minutes (3 minute run).

Example 1464-[[4-Cyclopropyl-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(116)

Step 1: Methyl4-bromo-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A vial charged with 2-methoxy-4-(trifluoromethoxy)phenol (647 mg, 3.11mmol), methyl 4-bromo-2,5-difluoro-benzoate (780 mg, 3.11 mmol), Cs₂CO₃(2.5 g, 7.7 mmol) and DMF (6.5 mL) was heated at 80° C. for 2 hours. Thereaction mixture was cooled to room temperature and diluted with ethylacetate and brine. The layers were separated and the organic layer waswashed with brine (3×), dried over Na₂SO₄, filtered and concentrated invacuo. Silica gel chromatography (0-5% ethyl acetate/hexanes) providedmethyl4-bromo-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (350mg, 26%). ESI-MS m/z calc. 437.97, found 441.2 (M+2)+; retention time(Method B): 2.13 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ7.79 (d, J=8.7 Hz, 1H), 7.22-7.16 (m, 2H), 7.06 (d, J=8.8 Hz, 1H),6.97-6.91 (m, 1H), 3.81 (s, 3H), 3.77 (s, 3H) ppm.

Step 2: Methyl4-cyclopropyl-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

To a round bottom flask equipped with a stir bar was added methyl4-bromo-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (345mg, 0.786 mmol) and bis(tri-t-butylphosphine)palladium(0) (210 mg, 0.411mmol). The flask was sealed with a septum, placed under N₂ atmosphereand THF (5 mL) was added. The mixture was cooled to 0° C. and a solutionof bromo(cyclopropyl)zinc (3.2 mL of 0.5 M in THF, 1.6 mmol) was addeddropwise. After 30 minutes the reaction was quenched with saturatedaqueous NH₄Cl solution and diluted with ethyl acetate. The layers wereseparated and the organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. Silica gel chromatography (0-5%ethyl acetate/hexanes) provided methyl4-cyclopropyl-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(221 mg, 70%) and an off white solid. ESI-MS m/z calc. 400.09, found401.3 (M+1)+; retention time (Method B): 2.18 minutes (3 minute run).

Step 3:4-Cyclopropyl-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicAcid

To a solution of methyl4-cyclopropyl-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(220 mg, 0.550 mmol) in THF (3 mL) and water (2 mL) was added NaOH (223mg, 5.58 mmol) and the reaction mixture was stirred at room temperaturefor 2 hours. The reaction mixture was cooled in an ice bath and quenchedwith 1 M HCl. The aqueous layer was extracted with dichloromethane,dried over MgSO₄, filtered and concentrated in vacuo to obtain4-cyclopropyl-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (173 mg, 81%). ESI-MS m/z calc. 386.07, found 387.1 (M+1)+;retention time (Method B): 1.95 minutes (3 minute run).

Step 4:4-[[4-Cyclopropyl-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(116)

A vial was charged with4-cyclopropyl-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (76 mg, 0.20 mmol),4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(prepared as described in Preparation 1, 65 mg, 0.20 mmol),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (2 mg, 0.005 mmol) in2-propanol (1.1 mL) and heated at 80° C. under an atmosphere of air for20 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was dissolved in dichloromethane andwashed with 1 M HCl. The organic layer was dried over MgSO₄, filteredand concentrated. Silica gel chromatography (0-60% ethylacetate-hexanes) provided4-[[4-cyclopropyl-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(44 mg, 44%). ESI-MS m/z calc. 505.12, found 506.3 (M+1)+; retentiontime (Method B): 1.93 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.77 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.06(d, J=2.8 Hz, 1H), 7.79 (dd, J=5.6, 2.2 Hz, 1H), 7.61 (s, 1H), 7.52 (d,J=10.0 Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.89(ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.58 (d, J=6.3 Hz, 1H), 3.73 (s, 3H),2.07 (ddd, J=13.6, 8.7, 5.2 Hz, 1H), 1.09-0.95 (m, 2H), 0.77-0.62 (m,2H) ppm.

Example 1474-[[2-[2-(Trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(158)

Step 1:4-[[2-Fluoro-5-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide

To a solution of 4-aminopyridine-2-carboxamide (565 mg, 4.12 mmol) andDIEA (1.33 g, 10.3 mmol) in NMP (10 mL) at 0° C. was added a solution of2-fluoro-5-(trifluoromethoxy)benzoyl chloride (1.00 g, 4.123 mmol) indichloromethane (5 mL) dropwise. The reaction was allowed to warm toroom temperature and stirred for 16 hours. The reaction mixture waspartitioned between ethyl acetate and water, and the layers separated.The organic layer was dried over Na₂SO₄, filtered and concentrated invacuo to obtain4-[[2-fluoro-5-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(850 mg, 60%). ESI-MS m/z calc. 343.05, found 344.1 (M+1)+; retentiontime (Method B): 0.51 minutes (3 minute run).

Step 2:4-[[2-[2-(Trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(158)

A mixture of4-[[2-fluoro-5-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(75 mg, 0.22 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol(prepared as described in Example 1, step 2, 46 mg, 0.22 mmol), K₂CO₃(91 mg, 0.66 mmol) in DMF (0.75 mL) was heated at 100° C. for 2 hours.The reaction mixture was cooled to room temperature, filtered anddiluted with DMSO (1 mL). HPLC purification (10-99% acetonitrile/5 mMHCl) provided4-[[2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(58 mg, 49%) as a white solid. ESI-MS m/z calc. 534.10, found 535.1(M+1)+; retention time (Method B): 1.84 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.32 (d,J=2.1 Hz, 1H), 8.10 (d, J=2.8 Hz, 1H), 7.88 (dd, J=5.5, 2.2 Hz, 1), 7.67(dd, J=22.1, 2.9 Hz, 2H), 7.53-7.44 (m, 1H), 7.32 (d, J=8.8 Hz, 1H),7.20 (d, J=2.8 Hz, 1H), 7.02 (ddq, J=8.8, 2.5, 1.2 Hz, 1H), 6.87 (d,J=9.0 Hz, 1H) ppm.

Example 148N-(2-Carbamoyl-5-methyl-4-pyridyl)-3-methoxy-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(131)

Step 1: Ethyl 3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate

A solution of 3,5-difluoro-2-(trifluoromethyl)pyridine (9.00 g, 49.16mmol) in THF (100 mL) was cooled to −78° C. A solution of LDA (27 mL of2 M in ethylbenzene/THF/heptane, 54 mmol) was added dropwise whilemaintaining the reaction internal temperature below −65° C. The mixturewas stirred at −78° C. for 40 minutes after the completion of the LDAaddition. The reaction mixture was then treated with ethyl chloroformate(6.1 mL, 64 mmol) dropwise over 10 minutes while keeping the internaltemperature below −65° C. The mixture was stirred at −78° C. for 30minutes then allowed to warm to room temperature over 1 hour. Themixture was quenched by addition of saturated aqueous NH₄Cl and dilutedwith ethyl acetate (100 mL). The organic layer was separated and washedwith water (2×) and brine, dried over MgSO₄, filtered and concentratedin vacuo. Purification by silica gel chromatography (0-5% ethylacetate/petroleum ether) provided ethyl3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate (7.4 g, 59%) as apale yellow oil. ESI-MS m/z calc. 255.03, retention time (Method F):0.94 minutes (1.5 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H),4.46 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H) ppm. ¹⁹F NMR (376 MHz,DMSO-d6) δ −64.15 (d, J=15.2 Hz), −116.78-−118.04 (m), −121.70 (qd,J=15.6, 5.8 Hz) ppm.

Step 2: Ethyl3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate

To a solution of ethyl3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate (1.87 g, 7.33mmol) and 4-(trifluoromethoxy)phenol (0.950 mL, 7.33 mmol) in DMA (20mL) at 0° C. was added Cs₂CO₃ (4.78 g, 14.7 mmol) in one portion. Thereaction mixture was allowed to warm to room temperature and stirred for1 hour. The mixture was diluted with water and extracted with ethylacetate. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. Purification by silica gel columnchromatography (0-10% ethyl acetate/hexanes) provided ethyl3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate(2.223 g, 73%). ESI-MS m/z calc. 413.04, found 414.2 (M+1)+; retentiontime (Method B): 2.16 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 8.50 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.38-7.31 (m, 2H), 4.31 (q,J=7.1 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H) ppm.

Step 3:3-Fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicAcid

To a flask charged with ethyl3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate(2.22 g, 5.37 mmol) in THF (22 mL) was added NaOH (20 mL of 3 M, 60mmol) and 500 mg of solid NaOH. The reaction mixture was stirred for 4hours at room temperature then cooled to 0° C. and quenched slowly with6 M HCl. The resulting precipitate was filtered and washed with water.The filtrate was extracted with dichloromethane and combined with thefiltered solid. The combined solution was dried over MgSO₄, filtered andconcentrated in vacuo to obtain3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (1.967 g, 95%). ESI-MS m/z calc. 385.01, found 386.0 (M+1)+;retention time (Method B): 1.73 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 8.40 (s, 1H), 7.50-7.43 (m, 2H), 7.38-7.30 (m, 2H) ppm.

Step 4:N-(2-Bromo-5-methyl-4-pyridyl)-3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide

To a solution of3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (250 mg, 0.649 mmol) in dichloromethane (4 mL) at 0° C. was addedDMF (6 μL, 0.07 mmol) and oxalyl chloride (278 mg, 0.190 mL, 2.19 mmol).The reaction was allowed to warm to room temperature and stirred for 3.5hours. The reaction mixture was concentrated in vacuo, dissolved indichloromethane (4.4 mL) and the solution was cooled to 0° C.2-Bromo-5-methyl-pyridin-4-amine (157 mg, 0.841 mmol) was added followedby triethylamine (346 mg, 0.477 μL, 3.42 mmol). The resulting mixturewas allowed to warm to room temperature over 16 hours. The reactionmixture was quenched with water (10 mL) and extracted withdichloromethane (2×10 mL). The combined organics were dried over MgSO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (0-20% ethyl acetate/petroleum ether) providedN-(2-bromo-5-methyl-4-pyridyl)-3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(181 mg, 47%). ESI-MS m/z calc. 552.98, found 554.0 (M+1)+; retentiontime (Method E): 1.33 minutes (5 minute run).

Step 5: Methyl4-[[3-methoxy-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate

To a solution ofN-(2-bromo-5-methyl-4-pyridyl)-3-fluoro-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(181 mg, 0.304 mmol) in methanol (8 mL) and triethylamine (65 mg, 0.64mmol) in a pressure vessel was added Pd(dppf)Cl₂.DCM (50 mg, 0.061mmol). Carbon monoxide was bubbled through the vigorously stirringreaction mixture for 5 minutes. The reaction vessel was sealed andheated at 75° C. for 16 hours. The reaction mixture was cooled to roomtemperature, filtered through a pad of Celite eluting with methanol andconcentrated in vacuo. Purification by silica gel chromatography (0-100%ethyl acetate/petroleum ether) provided methyl4-[[3-methoxy-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(51 mg, 31%) as a red solid. ESI-MS m/z calc. 545.10, found 546.0(M+1)+; retention time (Method F): 1.01 minutes (1.5 minute run). ¹⁹FNMR (471 MHz, CDCl₃) δ −58.01, −60.82 (d, J=12.9 Hz), −112.16-−112.24(m) ppm.

Step 6:N-(2-Carbamoyl-5-methyl-4-pyridyl)-3-methoxy-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(131)

A mixture of methyl4-[[3-methoxy-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(51 mg, 0.094 mmol) and ammonia (2.6 mL of 4 M in methanol, 10.40 mmol)was stirred at room temperature for 16 hours. SPM32 silica metalscavenger (150 mg) was added and the reaction was stirred for 15minutes. The mixture was filtered and the filtrate was concentrated invacuo. Purification by silica gel chromatography (0-100% ethylacetate/petroleum ether) providedN-(2-carbamoyl-5-methyl-4-pyridyl)-3-methoxy-5-[4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(33.2 mg, 62%) as a white solid. ESI-MS m/z calc. 530.10, found 531.0(M+1)+; retention time (Method E): 3.26 minutes (5 minute run). ¹H NMR(500 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.46 (d, J=4.0 Hz, 2H), 8.20 (s,1H), 8.13-7.91 (m, 1H), 7.60 (s, 1H), 7.59-7.43 (m, 2H), 7.36 (d, J=9.1Hz, 2H), 4.04 (s, 3H), 2.08 (s, 3H) ppm.

Example 149N-(3-Carbamoyl-4-fluoro-phenyl)-2-cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(46)

Step 1: Ethyl 2-bromo-3,5-difluoro-pyridine-4-carboxylate

2-Bromo-3,5-difluoro-pyridine (4.9 g, 25 mmol) was dissolved inanhydrous THF (20 mL) under a N₂ atmosphere and cooled to −78° C. in adry ice/acetone bath. A solution of LDA (2.7 g, 3.3 mL of 2 MTHF/heptane/benzene, 25 mmol) was further diluted with anhydrous THF (49mL) and this solution was added dropwise to the reaction mixture over aperiod of 1 hour while maintaining the internal temperature below −70°C. The reaction mixture was stirred at −78° C. for 1 hour, and was thentreated dropwise with a solution of ethyl chloroformate (7.5 g, 6.6 mL,69 mmol) in THF (6 mL) while maintaining the internal temperature below−70° C. The reaction mixture was then allowed to warm to roomtemperature. After 10 minutes at room temperature the reaction mixturewent from a clear solution to a slurry, which was then quenched with asaturated aqueous solution of NH₄Cl. The mixture was extracted withethyl acetate (2×), and the combined organics were dried over Na₂SO₄,filtered and concentrated to an orange oil in vacuo. Silica gelchromatography (0-3% ethyl acetate/hexanes) provided ethyl2-bromo-3,5-difluoro-pyridine-4-carboxylate (1.96 g, 29%) as a clearliquid. ESI-MS m/z calc. 264.95, found 267.9 (M+1); retention time(Method B): 1.49 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ8.62 (d, J=3.2 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H)ppm.

Step 2: Ethyl 2-cyclopropyl-3,5-difluoro-pyridine-4-carboxylate

To a flask charged with ethyl2-bromo-3,5-difluoro-pyridine-4-carboxylate (1.95 g, 7.33 mmol) andbis(tri-t-butylphosphine)palladium(0) (188 mg, 0.368 mmol) under anatmosphere of N₂ at 0° C. was added a solution of bromo(cyclopropyl)zinc(15 mL of 0.5 M in THF, 7.5 mmol) and the reaction mixture was allowedto gradually warmed to room temperature and stirred for 1 hour. Another100 mg of the catalyst and 2 mL of the bromo(cyclopropyl)zinc solutionwere added and stirred for 30 minutes at room temperature. The reactionmixture was quenched with 1 M HCl and the aqueous layer was extractedwith dichloromethane (3×). The combined organic layers were dried overMgSO₄, filtered and concentrated in vacuo. Silica gel chromatography(0-5% ethyl acetate/hexanes) provided ethyl2-cyclopropyl-3,5-difluoro-pyridine-4-carboxylate (917 mg, 55%). ESI-MSm/z calc. 227.075, found 228.1 (M+1)+; retention time (Method B): 1.7minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 4.43(q, J=7.1 Hz, 2H), 2.33 (dddd, J=12.8, 8.0, 4.8, 2.2 Hz, 1H), 1.32 (t,J=7.1 Hz, 3H), 1.10-1.02 (m, 2H), 0.98 (ddt, J=7.2, 4.6, 2.5 Hz, 2H)ppm.

Step 3: Ethyl2-cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylate

A mixture of ethyl 2-cyclopropyl-3,5-difluoro-pyridine-4-carboxylate(520 mg, 2.29 mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (preparedas described in Example 2, step 2, 476 mg, 2.29 mmol) in DMF (5.2 mL) at0° C. was treated with Cs₂CO₃ (1.20 g, 3.68 mmol) in one portion. Themixture was gradually warmed to room temperature and stirred for 3 days.The mixture was diluted with water and extracted with ethyl acetate(3×20 mL). The combined organic layers were dried over MgSO₄ andconcentrated in vacuo. Silica gel chromatography (1-5% ethylacetate/hexanes) provided ethyl2-cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylate(520 mg, 55%). ESI-MS m/z calc. 415.10, found 416.2 (M+1)+; retentiontime (Method A): 0.82 minutes (1.2 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 8.53 (s, 1H), 7.17 (d, J=2.7 Hz, 1H), 6.87 (ddq, J=8.9, 2.3,1.1 Hz, 1H), 6.73 (d, J=8.9 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.85 (s,3H), 2.09 (tt, J=8.0, 4.9 Hz, 1H), 1.01 (t, J=7.1 Hz, 3H), 0.94-0.84 (m,4H) ppm.

Step 4:2-Cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylicAcid

To a solution of ethyl2-cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylate(225 mg, 0.542 mmol) in methanol (2.5 mL) was added NaOH (1 mL of 6 M, 6mmol) at 0° C. and the reaction mixture was gradually warmed to roomtemperature and stirred for 30 minutes. The solvent was evaporated andthe residue taken up in water and cooled to 0° C. A solution of 6 M HClwas added slowly and the resulting precipitate was filtered and washedwith water. The residue was taken up in dichloromethane/ethyl acetate,dried over MgSO₄, filtered and concentrated in vacuo to provide2-cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylicacid (171 mg, 82%). ESI-MS m/z calc. 387.07, found 388.2 (M+1)+;retention time (Method A): 0.7 minutes (1.2 minute run).

Step 5:2-Cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonylchloride

To a suspension of2-cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylicacid (167 mg, 0.431 mmol) and DMF (10 μL, 0.13 mmol) in dichloromethane(2 mL) at 0° C. under N₂ atmosphere was added oxalyl chloride (0.115 mL,1.32 mmol) dropwise over 1 minute. The ice bath was removed and replacedwith a room-temperature water bath. The reaction mixture was stirred atroom temperature for 30 minutes. The reaction mixture was concentratedin vacuo. The product2-cyclopropyl-3-fluoro-5-(2-methoxy-4-(trifluoromethoxy)phenoxy)isonicotinoylchloride was used directly for the next step.

Step 6:N-(3-Carbamoyl-4-fluoro-phenyl)-2-cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(46)

To a vial charged with 5-amino-2-fluoro-benzamide (23 mg, 0.15 mmol) andDIEA (38 mg, 0.052 mL, 0.30 mmol) in THF (0.2 mL) at 0° C. was added asolution of2-cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carbonylchloride (60 mg, 0.15 mmol) in dichloromethane dropwise. The reactionmixture was gradually warmed to room temperature and stirred for 18hours. The reaction mixture was quenched with water and the aqueouslayer was extracted with dichloromethane. The organic layer was driedover MgSO₄, filtered and concentrated in vacuo. The crude material wasdissolved in DMF/methanol, filtered (syringe filter) and purified byHPLC (10-99% acetonitrile/5 mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-2-cyclopropyl-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(27 mg, 34%). ESI-MS m/z calc. 523.11, found 524.2 (M+1)+; retentiontime (Method B): 1.69 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.93 (s, 1H), 8.54 (s, 1H), 7.79 (dd, J=6.4, 2.8 Hz, 1H), 7.69 (s,2H), 7.55 (ddd, J=9.0, 4.4, 2.8 Hz, 1H), 7.23 (dd, J=10.1, 8.9 Hz, 1H),7.03 (d, J=2.7 Hz, 1H), 6.82 (ddd, J=8.9, 2.5, 1.2 Hz, 1H), 6.75 (d,J=8.9 Hz, 1H), 3.71 (s, 3H), 2.09 (ddd, J=13.1, 8.0, 4.9 Hz, 1H), 0.93(qd, J=6.2, 2.4 Hz, 2H), 0.88-0.82 (m, 2H) ppm.

Example 150N-(3-Carbamoyl-4-fluoro-phenyl)-6-(2,3-dihydrobenzofuran-7-yloxy)-2-fluoro-3-(trifluoromethyl)benzamide(58)

To a pressure flask was added6-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-3-(trifluoromethyl)benzamide(prepared as described in Example 140, step 1, 100 mg, 0.236 mmol)),2,3-dihydrobenzofuran-7-ol (34 mg, 0.25 mmol), Cs₂CO₃ (105 mg, 0.323mmol) and toluene (3 mL). The reaction mixture was bubbled with N₂ gasfor 5 minutes then treated with copper (I) iodide (34 mg, 0.18 mmol).The flask was flushed with N₂, sealed and heated at 100° C. withvigorous stirring for 1.5 hours. The mixture was cooled and diluted withethyl acetate and water. The two layers were separated and the aqueouslayer was extracted with additional ethyl acetate (3×). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. HPLC purification (1-99% acetonitrile/5 mM HCl) providedN-(3-carbamoyl-4-fluoro-phenyl)-6-(2,3-dihydrobenzofuran-7-yloxy)-2-fluoro-3-(trifluoromethyl)benzamide(5.1 mg, 4%). ESI-MS m/z calc. 478.09, found 479.1 (M+1)+; retentiontime (Method C): 2.17 minutes (5 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.04 (s, 1H), 8.00 (dd, J=6.5, 2.8 Hz, 1H), 7.84-7.67 (m, 4H),7.36-7.23 (m, 1H), 7.20 (dd, J=7.3, 1.2 Hz, 1H), 7.08-6.96 (m, 1H),6.96-6.84 (m, 1H), 6.69 (d, J=8.8 Hz, 1H), 4.56 (t, J=8.7 Hz, 2H), 3.25(t, J=8.7 Hz, 2H) ppm.

Example 151N-(3-Carbamoyl-4-fluoro-phenyl)-2-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)benzamide(39)

N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(trifluoromethyl)benzamide(prepared as described in Example 138, step 1, 50 mg, 0.15 mmol),4-(trifluoromethoxy)phenol (53 mg, 0.038 mL, 0.30 mmol) and Cs₂CO₃ (98mg, 0.30 mmol) were combined in DMF (1.0 mL) and heated at 100° C. for 1hour. The reaction was cooled to room temperature, filtered and dilutedwith DMSO (0.5 mL). HPLC purification (1-70% acetonitrile/5 mM HCl)providedN-(3-carbamoyl-4-fluorophenyl)-2-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)benzamide(17 mg, 21%). ESI-MS m/z calc. 502.07, found 503.2 (M+1)+; retentiontime (Method B): 1.64 minutes (3 minute run).

Example 1524-[[2-[4-(Trifluoromethoxy)phenoxy]-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(160)

This compound was made in an analogous fashion to Example 91 above,except employing 4-(trifluoromethoxy)phenol in the displacement step(Step 2). The yield of the desired product after purification was 14 mg(20%). ESI-MS m/z calc. 553.33, found 554.1 (M+1)+; retention time(Method B): 1.84 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.47 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H), 8.10 (d,J=18.6 Hz, 2H), 7.80-7.71 (m, 2H), 7.69 (d, J=2.7 Hz, 1H), 7.55-7.39 (m,2H), 7.39-7.24 (m, 2H) ppm.

Example 153N-(3-Carbamoyl-4-fluoro-phenyl)-4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxamide(36)

Step 1: Methyl6-bromo-4-[3-chloro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

To a flask charged with methyl 6-bromo-4-chloro-pyridine-3-carboxylate(2.80 g, 11.2 mmol) and Cs₂CO₃ (9.5 g, 29 mmol) in DMF (28 mL) at 0° C.was added 3-chloro-4-(trifluoromethoxy)phenol (2.37 g, 11.2 mmol). Thereaction mixture was gradually warmed to room temperature, stirred for 3hours and quenched with water. The aqueous layer was extracted withethyl acetate (3×). The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-10% ethyl acetate/hexanes) provided methyl6-bromo-4-[3-chloro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(2.52 g, 53%). ESI-MS m/z calc. 424.92, found 428.1 (M+2)+; retentiontime (Method B): 2.01 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 8.77 (s, 1H), 7.71-7.65 (m, 2H), 7.35-7.30 (m, 2H), 3.82 (s, 3H) ppm.

Step 2: Methyl4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxylate

To a vial containing methyl6-bromo-4-[3-chloro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(490 mg, 1.15 mmol) and bis(tri-t-butylphosphine)palladium (0) (209 mg,0.409 mmol) at 0° C. under N₂ atmosphere was added a solution ofbromo(cyclopropyl)zinc (2.7 mL of 0.5 M in THF, 1.350 mmol) dropwise.The reaction mixture was stirred for 10 minutes then quenched withsaturated aqueous NH₄Cl solution. The mixture was extracted with ethylacetate (2×) and the combined organics were dried over Na₂SO₄, filteredand concentrated in vacuo. Silica gel chromatography (0-15% ethylacetate/hexanes) provided methyl4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxylate(348 mg, 78%) as a yellow oil. ESI-MS m/z calc. 387.04, found 388.2(M+1)+; retention time (Method A): 0.71 minutes (1.2 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.67-7.62 (m, 1H), 7.59 (d, J=2.9 Hz,1H), 7.23 (dd, J=9.0, 2.9 Hz, 1H), 7.02 (s, 1H), 3.77 (s, 3H), 2.15 (p,J=6.4 Hz, 1H), 0.99 (d, J=6.4 Hz, 4H) ppm.

Step 3:4-[3-Chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxylicAcid

To a solution of methyl4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxylate(348 mg, 0.898 mmol) in methanol (4 mL) and water (2 mL) was added NaOH(580 mg, 14.5 mmol) and the reaction mixture was stirred at roomtemperature for 40 minutes. The solvents were removed under reducedpressure and the residue was dissolved in water. The solution was cooledto 0° C. and treated dropwise with 6 M HCl until a white precipitateformed. The solid was collected by vacuum filtration, washed with waterand then dried in a desiccator filled with DrieRite® under high vacuumfor 16 hours to provide4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxylicacid (308 mg, 92%). ESI-MS m/z calc. 373.03, found 374.1 (M+1)+;retention time (Method A): 0.58 minutes (1.2 minute run).

Step 4:4-[3-Chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carbonylchloride

To a solution of4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxylicacid (308 mg, 0.824 mmol) and DMF (7 μL, 0.08 mmol) in dichloromethane(3 mL) at 0° C. under a N₂ atmosphere was added oxalyl chloride (0.072mL, 0.83 mmol) as a solution in dichloromethane (1 mL) dropwise. After 5minutes the reaction was allowed to warm to room temperature and stirredfor 30 minutes. This reaction solution4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carbonylchloride was used directly in the next step.

Step 5:N-(3-Carbamoyl-4-fluoro-phenyl)-4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxamide(36)

To a solution of 5-amino-2-fluoro-benzamide (48 mg, 0.31 mmol) and DIEA(0.137 mL, 0.787 mmol) in anhydrous THF (1.5 mL) at 0° C. under a N₂atmosphere was added a solution of4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carbonylchloride (103 mg, 0.262 mmol) in dichloromethane (1.3 mL) dropwise. Thereaction mixture was allowed to slowly warm to room temperature andcontinued to stir at room temperature for 16 hours. The reaction mixturewas partitioned between dichloromethane and water. The layers wereseparated and the aqueous layer was extracted once more withdichloromethane. The combined organics were dried over Na₂SO₄, filteredand concentrated in vacuo. Silica gel chromatography (0-60% ethylacetate/dichloromethane) providedN-(3-carbamoyl-4-fluoro-phenyl)-4-[3-chloro-4-(trifluoromethoxy)phenoxy]-6-cyclopropyl-pyridine-3-carboxamide(28.4 mg, 21%). ESI-MS m/z calc. 509.07, found 510.2 (M+1)+; retentiontime (Method B): 1.46 minutes (3 minute run).

Example 1544-[[5-Chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(150)

Step 1: 5-Chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde

A mixture of 2-methoxy-4-(trifluoromethoxy)phenol (prepared as describedin Example 2, step 2, 2.00 g, 8.42 mmol), 5-chloro-2-fluoro-benzaldehyde(1.34 g, 8.45 mmol) and Cs₂CO₃ (3.29 g, 10.1 mmol) in DMF (10 mL) washeated at 100° C. for 4 hours. The reaction mixture was cooled to roomtemperature and partitioned between ethyl acetate (50 mL) and water (30mL). The organic layer was separated and washed with water (2×30 mL) andbrine, dried over MgSO₄, filtered and concentrated in vacuo. Silica gelcolumn chromatography (0-5% ethyl acetate/petroleum ether) provided5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde (2.2 g,73%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.75(d, J=2.8 Hz, 1H), 7.62 (dd, J=8.9, 2.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H),7.27 (d, J=2.7 Hz, 1H), 7.04 (ddd, J=8.7, 2.7, 1.2 Hz, 1H), 6.77 (d,J=8.9 Hz, 1H), 3.79 (s, 3H) ppm.

Step 2: 5-Chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic Acid

To a mixture of5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde (2.2 g,6.2 mmol), sodium dihydrogenphosphate (740 mg, 6.17 mmol) and2-methyl-2-butene (13.8 mL of 2 M in THF, 27.6 mmol) in tert-butylalcohol (20 mL) and water (14 mL) at −5° C. (ice/brine bath) was addedsodium chlorite (835 mg, 7.39 mmol) portionwise over 30 minutes. Themixture was allowed to warm to room temperature and stirred for 1 hour.The reaction mixture was acidified to pH1-2 using 2 M HCl andpartitioned with ethyl acetate. The organic layer was separated, driedover MgSO₄, filtered and concentrated in vacuo to afford5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (2.24 g,100%) as a white solid. ESI-MS m/z calc. 362.01, found 364.9 (M+1)+;361.0 (M−1)−; retention time (Method E): 0.68 minutes (5 minute run). ¹HNMR (500 MHz, DMSO-d6) δ 12.90 (s, 1H), 7.77 (d, J=2.8 Hz, 1H), 7.52(dd, J=8.9, 2.8 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H),6.95 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H), 3.79 (s, 3H)ppm.

Step 3:N-(2-Bromo-5-methyl-4-pyridyl)-5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide

To a solution of5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (300 mg,0.827 mmol) in dichloromethane (5 mL) at 0° C. was added DMF (7 μL, 0.09mmol) and oxalyl chloride (243 μL, 2.79 mmol) dropwise. The reactionmixture was stirred and warmed to room temperature over 3.5 hours. Thereaction mixture was concentrated in vacuo, dissolved in dichloromethane(5 mL) and cooled in an ice bath. 2-Bromo-5-methyl-pyridin-4-amine (201mg, 1.08 mmol) was added followed by triethylamine (0.610 mL, 4.38mmol). The resulting mixture was stirred and warmed to room temperatureover 16 hours. The reaction mixture was diluted with water (10 mL) andextracted with dichloromethane (2×10 mL). The combined organics weredried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-60% ethyl acetate/petroleum ether) providedN-(2-bromo-5-methyl-4-pyridyl)-5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(276 mg, 63%). ESI-MS m/z calc. 529.98, found 533.0 (M+1)+; retentiontime (Method E): 1.19 minutes (5 minute run).

Step 4: Methyl4-[[5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

To a solution ofN-(2-bromo-5-methyl-4-pyridyl)-5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide(276 mg, 0.519 mmol) in methanol (5 mL) and triethylamine (112 mg, 1.11mmol) was added Pd(dppf)Cl₂.DCM (86 mg, 0.11 mmol). Carbon monoxide gaswas bubbled through the vigorously stirring reaction mixture for 5minutes. The reaction mixture was then heated at 75° C. under carbonmonoxide atmosphere (balloon) for 16 hours. The reaction was cooled toroom temperature, filtered through a pad of Celite eluting with methanoland concentrated in vacuo. Silica gel chromatography (30-80% ethylacetate/petroleum ether) provided methyl4-[[5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(229 mg, 86%) as a yellow oil. ESI-MS m/z calc. 510.08, found 511.0(M+1)+; retention time (Method E): 1.08 minutes (5 minute run).

Step 5:4-[[5-Chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(150)

A mixture of methyl4-[[5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(229 mg, 0.448 mmol) and ammonia (12.6 mL of 4 M in methanol, 50.4 mmol)was stirred at room temperature for 16 hours. The reaction was filteredand concentrated in vacuo. The residue was purified by HPLC(acetonitrile/0.1% ammonium hydroxide) to provide the product as a whitesolid (140 mg). Further purification by normal phase SFC (Chiralpak IB(250×20 mm ID) 5 μm particle (Chiral Technologies Europe pn: 81445) witha Gemini-NX (10×10 mm) guard column (Phenomenex pn: AJ0-8369), and anisocratic run 15% of methanol with 20 mM ammonia solution (mobile phaseB) over 6 minutes; Mobile phase A=Supercritical Liquid Carbon Dioxide(58-60 bar); Mobile phase B=Methanol with 20 mM Ammonium hydroxide; Flowrate=100 mL/min, column temperature=40° C.) provided4-[[5-chloro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(87.6 mg, 39%) as a white solid. ESI-MS m/z calc. 495.08, found 496.0(M+1)+; retention time (Method E): 3.58 minutes (5 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.71 (s, 1H), 8.43 (s, 1H), 8.05 (d,J=2.9 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H), 7.68-7.37 (m, 3H), 7.26 (d, J=2.8Hz, 1H), 7.06 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.78 (d, J=8.9 Hz, 1H),3.79 (s, 3H), 2.25 (s, 3H) ppm.

Example 155N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(142)

N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(2, 40 mg, 0.073 mmol) was dissolved in dichloromethane (0.8 mL) andcooled to −78° C. (dry ice/acetone bath). The solution was treateddropwise with a solution of BBr₃ (363 μL of 1 M in dichloromethane,0.363 mmol) forming a yellow precipitate. Stirring was continued for 10minutes, then the cooling bath was removed and the reaction mixture wasallowed to warm to room temperature and stirred for 20 minutes(precipitate forms). The reaction mixture was quenched with a 1:1solution of methanol (0.7 mL)/1 M NaOH NaOH (0.7 mL). The reactionmixture was diluted with dichloromethane and washed with saturatedNaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by HPLC (1-99% acetonitrile/5 mM HCl) providedN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(13 mg, 33%) as a pale yellow solid. ESI-MS m/z calc. 536.06, found537.1 (M+1)+; retention time (Method B): 1.71 minutes (3 minute run). ¹HNMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.60 (s, 1H), 8.00 (dd, J=6.4,2.8 Hz, 1H), 7.86-7.76 (m, 2H), 7.70 (d, J=20.9 Hz, 2H), 7.30 (dt,J=9.5, 5.1 Hz, 2H), 6.97 (d, J=2.9 Hz, 1H), 6.89 (dd, J=8.7, 2.8 Hz,1H), 6.64 (d, J=8.9 Hz, 1H) ppm.

Example 1564-[[2-Fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(214)

To a solution of4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(6, 200 mg, 0.373 mmol) in dichloromethane (4 mL) at −78° C. was added asolution of BBr₃ (1.5 mL of 1 M in dichloromethane, 1.5 mmol) dropwise.The reaction mixture was stirred at −78° C. for 5 minutes then allowedto warm to room temperature and stirred for 3 hours. The reaction wasdiluted with dichloromethane and washed with 50% saturated NaHCO₃,water, and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. HPLC purification (10-99% acetonitrile/5 mM HCl)provided4-[[2-fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(115.2 mg, 59%). ESI-MS m/z calc. 519.06, found 520.1 (M+1)+; retentiontime (Method B): 1.67 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 11.42 (s, 1H), 10.62 (s, 1H), 8.56 (d, J=5.4 Hz, 1H), 8.33 (d, J=2.1Hz, 1H), 8.10 (d, J=2.9 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.82 (t,J=8.6 Hz, 1H), 7.66 (d, J=2.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.99-6.92(m, 1H), 6.91-6.85 (m, 1H), 6.67 (d, J=8.9 Hz, 1H) ppm.

Example 157N-(3-Carbamoyl-4-fluoro-phenyl)-6-cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(42)

Step 1: Methyl6-bromo-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

To a flask charged with methyl 6-bromo-4-chloro-pyridine-3-carboxylate(prepared as described in Example 135, step 1, 2.6 g, 10 mmol) andCs₂CO₃ (8.5 g, 26 mmol) in DMF (26 mL) at 0° C. was added3-fluoro-4-(trifluoromethoxy)phenol (2.0 g, 10 mmol). The reactionmixture was allowed to warm to room temperature over 3 hours and dilutedwith water. The resulting precipitate was filtered and washed withwater. The solid was dissolved in dichloromethane, dried over MgSO₄,filtered and concentrated in vacuo. Silica gel chromatography (0-20%ethyl acetate/hexanes) provided methyl6-bromo-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(2.8 g, 68%). ESI-MS m/z calc. 408.95, found 410.2 (M+1)+; retentiontime (Method B): 1.88 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 8.77 (s, 1H), 7.69 (tq, J=9.0, 1.1 Hz, 1H), 7.56 (dd, J=11.1, 2.8 Hz,1H), 7.31 (s, 1H), 7.18 (ddd, J=9.1, 2.9, 1.6 Hz, 1H), 3.82 (s, 3H) ppm.

Step 2: Methyl6-cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate

To a flask charged with methyl6-bromo-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(1.00 g, 2.44 mmol) and bis(tri-t-butylphosphine)palladium (0) (223 mg,0.436 mmol) at 0° C. under an atmosphere of N₂ was added a solution ofbromo(cyclopropyl)zinc (7.3 mL of 0.5 M in THF, 3.7 mmol). The reactionmixture was gradually warmed to room temperature and stirred for 1 hour.The reaction mixture was quenched with 1 M HCl and the aqueous layer wasextracted with dichloromethane (3×). The combined organic layers weredried over MgSO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-10% ethyl acetate/hexanes) provided methyl6-cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(576 mg, 64%). ESI-MS m/z calc. 371.07, found 372.1 (M+1)+; retentiontime (Method B): 1.66 minutes (3 minute run).

Step 3:6-Cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicAcid

To a solution of methyl6-cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(575 mg, 1.55 mmol) in methanol (6 mL) at 0° C. was added NaOH (2.8 mLof 6 M, 16.8 mmol) and the reaction mixture was gradually warmed to roomtemperature and stirred for 30 minutes. The solvent was removed invacuo. The residue was dissolved in water, cooled to 0° C. and treateddropwise with 6 M HCl. The resulting precipitate was filtered and washedwith water. The solid was dissolved in dichloromethane/ethyl acetate,dried over MgSO₄, filtered and concentrated to provide6-cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (550 mg, 99%). ESI-MS m/z calc. 357.06, found 358.1 (M+1)+;retention time (Method B): 1.28 minutes (3 minute run).

Step 4:6-Cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carbonylchloride

To a mixture of6-cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylicacid (472 mg, 1.32 mmol) and DMF (10 μL, 0.13 mmol) in dichloromethane(5 mL) at 0° C. under a N₂ atmosphere was added oxalyl chloride (0.115mL, 1.32 mmol) over 1 minute. The ice bath was removed and replaced witha room-temperature water bath and stirred for 3 hours. The reaction wasconcentrated in vacuo, dried on high vacuum for 30 minutes and was useddirectly for the next step.

Step 5:N-(3-Carbamoyl-4-fluoro-phenyl)-6-cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(42)

To a mixture of 5-amino-2-fluoro-benzamide (27 mg, 0.18 mmol) and DIEA(62 mg, 0.48 mmol) in dichloromethane (0.6 mL) at 0° C. was added6-cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carbonylchloride (60 mg, 0.16 mmol) as a solution in dichloromethane (0.6 mL).The reaction mixture was stirred for 1 hour, then quenched with methanoland purified by HPLC (1-99% acetonitrile/5 mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-6-cyclopropyl-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide(15.8 mg, 17%). ESI-MS m/z calc. 493.10, found 494.2 (M+1)+; retentiontime (Method B): 1.38 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.57 (s, 1H), 8.65 (s, 1H), 7.97 (dd, J=6.5, 2.8 Hz, 1H), 7.78 (ddd,J=9.0, 4.4, 2.7 Hz, 1H), 7.73-7.63 (m, 3H), 7.54 (dd, J=11.1, 2.8 Hz,1H), 7.31-7.17 (m, 2H), 6.99 (s, 1H), 2.25-2.12 (m, 1H), 1.07-0.98 (m,4H) ppm.

Example 158N-(3-Carbamoyl-4-fluoro-phenyl)-2-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)benzamide(41)

N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(trifluoromethyl)benzamide(prepared as described in Example 138, Step 1, 50 mg, 0.15 mmol),4-fluoro-2-methyl-phenol (37 mg, 0.29 mmol) and Cs₂CO₃ (95 mg, 0.29mmol) were combined in DMF (1.0 mL) and heated at 100° C. for 1 hour.The reaction was cooled to room temperature, diluted with DMSO andfiltered. HPLC purification (1-70% acetonitrile/5 mM HCl) providedN-(3-carbamoyl-4-fluoro-phenyl)-2-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)benzamide(21.8 mg, 33%). ESI-MS m/z calc. 450.10, found 451.2 (M+1)+; retentiontime (Method B): 1.52 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 10.86 (s, 1H), 7.96 (dd, J=6.4, 2.8 Hz, 1H), 7.75-7.70 (m, 2H), 7.69(s, 1H), 7.62-7.53 (m, 2H), 7.27 (dd, J=10.1, 8.9 Hz, 1H), 7.22 (d,J=9.1 Hz, 1H), 7.13-7.09 (m, 2H), 7.01-6.96 (m, 1H), 2.15 (s, 3H) ppm.

Example 1594-[[5-(Trifluoromethoxy)-2-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(156)

A mixture of4-[[2-fluoro-5-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(prepared as described in Example 147, Step 1, 75 mg, 0.22 mmol)),4-(trifluoromethoxy)phenol (39 mg, 0.22 mmol), K₂CO₃ (91 mg, 0.66 mmol)in DMF (0.75 mL) was heated at 100° C. for 1 hour. The reaction wasfiltered, diluted with DMSO (1 mL) and purified by HPLC (1-99%acetonitrile/5 mM HCl) to provide4-[[5-(trifluoromethoxy)-2-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(25 mg, 22%) as a white solid. ESI-MS m/z calc. 501.08, found 502.1(M+1)+; retention time (Method B): 1.79 minutes (3 minute run).

Example 160N-(3-Carbamoyl-4-fluoro-phenyl)-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]-6-isopropyl-pyridine-3-carboxamide(33)

Step 1: Methyl4-[3-fluoro-4-(trifluoromethoxy)phenoxy]-6-isopropyl-pyridine-3-carboxylate

To a flask charged with methyl6-bromo-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate(prepared as described in Example 157, Step 1, 1 g, 2 mmol) andbis(tri-tert-butylphosphine)palladium(0) (375 mg, 0.734 mmol) at 0° C.under an N₂ atmosphere was added a solution of bromo(isopropyl)zinc (7.5mL of 0.5 M in THF, 3.75 mmol). The reaction mixture was graduallywarmed to room temperature and stirred for 1 hour. The reaction mixturewas loaded directly onto a silica gel column and eluted using a 0-10%ethyl acetate/hexanes gradient. Product containing fractions wereconcentrated in vacuo and repurified using silica gel chromatography(0-10% ethyl acetate/hexanes) to obtain methyl4-[3-fluoro-4-(trifluoromethoxy)phenoxy]-6-isopropyl-pyridine-3-carboxylate(583 mg, 83%). ESI-MS m/z calc. 373.09, found 374.2 (M+1)+; retentiontime (Method B): 1.66 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6)δ 8.91 (s, 1H), 7.64 (tq, J=8.9, 1.0 Hz, 1H), 7.44 (dd, J=11.3, 2.9 Hz,1H), 7.04 (ddd, J=9.0, 2.9, 1.6 Hz, 1H), 6.95 (s, 1H), 3.78 (s, 3H),3.03 (h, J=6.9 Hz, 1H), 1.18 (d, J=6.9 Hz, 6H) ppm.

Step 2:N-(3-Carbamoyl-4-fluoro-phenyl)-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]-6-isopropyl-pyridine-3-carboxamide(33)

A microwave vial was charged with methyl4-[3-fluoro-4-(trifluoromethoxy)phenoxy]-6-isopropyl-pyridine-3-carboxylate(40 mg, 0.11 mmol), 1,4-diazabicyclo[2.2.2]octane trimethylalumane (43mg, 0.17 mmol) and 5-amino-2-fluoro-benzamide (17 mg, 0.11 mmol). Thereaction vial was evacuated and flushed with N₂. THF (800 μL) was addedand the reaction again was evacuated and flushed with N₂. The reactionmixture was subjected to microwave irradiation at 120° C. for 60minutes, then was cooled to room temperature and carefully quenched with1 M HCl. The aqueous layer was extracted with dichloromethane and theorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.Purification by HPLC (1-99% acetonitrile/5 mM HCl) providedN-(3-carbamoyl-4-fluoro-phenyl)-4-[3-fluoro-4-(trifluoromethoxy)phenoxy]-6-isopropyl-pyridine-3-carboxamide(6.1 mg, 11%). ESI-MS m/z calc. 495.12, found 496.3 (M+1)+; retentiontime (Method B): 1.4 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ10.69 (d, J=5.2 Hz, 1H), 8.79 (d, J=3.1 Hz, 1H), 7.98 (dd, J=6.4, 2.8Hz, 1H), 7.77 (ddd, J=7.7, 4.4, 2.9 Hz, 1H), 7.70 (t, J=8.0 Hz, 3H),7.54 (dd, J=11.0, 2.8 Hz, 1H), 7.33-7.13 (m, 2H), 7.00 (d, J=3.9 Hz,1H), 3.10 (p, J=7.2 Hz, 1H), 1.22 (dd, J=6.9, 1.1 Hz, 6H) ppm.

Example 161N-(3-Carbamoyl-4-fluoro-phenyl)-2-(2,4-dimethoxyphenoxy)-6-(trifluoromethyl)benzamide(38)

This compound was made in an analogous fashion to Example 158 exceptemploying 2,4-dimethoxyphenol in the fluorine-displacement step. Theyield of the desired product after purification was 17.7 mg (23%).ESI-MS m/z calc. 478.12, found 479.2 (M+1)+; retention time (Method B):1.44 minutes (3 minute run).

Example 1624-[[2-(4-Fluoro-2-methoxy-phenoxy)-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(148)

This compound was made in an analogous fashion to Example 143 exceptemploying 4-fluoro-2-methoxy-phenol in the fluorine-displacement step(Step 3). The yield of the desired product after purification was 44.3mg (43%) as a white solid. ESI-MS m/z calc. 465.10, found 466.1 (M+1)+;retention time (Method B): 1.66 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 10.98 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.35 (d, J=2.1 Hz,1H), 8.25-8.06 (m, 1H), 7.90 (dd, J=5.6, 2.2 Hz, 1H), 7.79 (d, J=8.4 Hz,1H), 7.66 (d, J=2.7 Hz, 1H), 7.33 (dd, J=8.9, 5.9 Hz, 1H), 7.20 (ddq,J=8.4, 2.3, 1.2 Hz, 1H), 7.13 (dd, J=10.6, 2.9 Hz, 1H), 6.86 (td, J=8.5,2.9 Hz, 1H), 6.56 (dd, J=2.2, 1.0 Hz, 1H), 3.74 (s, 3H) ppm.

Example 163N-(3-Carbamoyl-4-fluoro-phenyl)-2-(4-fluorophenoxy)-6-(trifluoromethyl)benzamide(37)

This compound was made in an analogous fashion to Example 138 exceptemploying 4-fluorophenol in the fluorine-displacement step (Step 2). Theyield of the desired product after purification was 17.6 mg (27%).ESI-MS m/z calc. 436.08, found 437.2 (M+1)+; retention time (Method B):1.43 minutes. ESI-MS m/z calc. 465.10, found 466.1 (M+1)+; retentiontime (Method B): 1.66 minutes (3 minute run).

Example 1644-[[2-(4-Fluoro-2-methoxy-phenoxy)-5-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(157)

This compound was made in an analogous fashion to Example 147 exceptemploying 4-fluoro-2-methoxy-phenol in the fluorine-displacement step(Step 2). The yield of the desired product after purification was 9.3 mg(9%) as a white solid. ESI-MS m/z calc. 465.10, found 466.3 (M+1)+;retention time (Method B): 1.65 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 11.03 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.35 (d, J=2.1 Hz,1H), 8.15 (s, 1H), 7.90 (dd, J=5.6, 2.2 Hz, 1H), 7.73-7.65 (m, 2H), 7.46(ddd, J=9.1, 3.1, 1.0 Hz, 1H), 7.30 (dd, J=8.9, 5.9 Hz, 1H), 7.13 (dd,J=10.7, 2.9 Hz, 1H), 6.85 (td, J=8.5, 2.9 Hz, 1H), 6.76 (d, J=9.1 Hz,1H), 3.74 (s, 3H) ppm.

Example 165N-(3-Carbamoyl-4-fluoro-phenyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(138)

Step 1:3-Methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylicAcid

To methyl3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylate(prepared as described in Example 119, Step 2, 300 mg, 0.831 mmol) wasadded a solution of sodium methoxide (8.5 mL of 0.5 M in methanol, 4.25mmol) and the mixture was stirred at 80° C. for 2 hours under argonatmosphere. The reaction was concentrated in vacuo to provide crudemethyl3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylateas a waxy solid. The solid was taken up in THF (7.6 mL), treated withaqueous NaOH (415 μL of 2 M, 0.83 mmol) and stirred at room temperaturefor 2 hours. The reaction mixture was concentrated in vacuo to provide3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylicacid (280 mg, 94%) which was taken directly to the next step. ESI-MS m/zcalc. 359.06, found 360.0 (M+1)+; retention time (Method F): 0.52minutes (1.5 minute run).

Step 2:N-(3-Carbamoyl-4-fluoro-phenyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(138)

To a solution of3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxylicacid (100 mg, 0.278 mmol) in dichloromethane (2 mL) at 0° C. was addedDMF (10 μL, 0.13 mmol) and oxalyl chloride (81 μL, 0.93 mmol) dropwise.The reaction mixture was stirred for 2 hours then concentrated in vacuoto afford the acid chloride as a white waxy solid. The solid wasdissolved in dichloromethane (2 mL) and added to a solution of5-amino-2-fluoro-benzamide dihydrochloride (83 mg, 0.37 mmol) andtriethylamine (241 μL, 1.73 mmol) in dichloromethane (3 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature over 16 hours,then concentrated in vacuo and purified by HPLC to provideN-(3-carbamoyl-4-fluoro-phenyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-4-carboxamide(8.2 mg, 6%) as a white solid. ESI-MS m/z calc. 495.11, found 495.96(M+1)+; 494.61 (M−1)−; retention time (Method E): 2.57 minutes (5 minuterun). ¹H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.08 (s, 1H), 7.73 (dd,J=6.5, 2.8 Hz, 1H), 7.54-7.39 (m, 4H), 7.06-6.91 (m, 3H), 6.72 (ddq,J=8.9, 2.4, 1.2 Hz, 1H), 3.71 (s, 3H), 3.55 (s, 3H) ppm.

Example 1664-[[4-(Trifluoromethoxy)-2-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(149)

This compound was made in an analogous fashion to Example 143 exceptemploying 4-(trifluoromethoxy)phenol in the fluorine-displacement step(Step 3). The yield of the desired product after purification was 45 mg(38%) as a white solid. ESI-MS m/z calc. 501.08, found 502.1 (M+1)+;retention time (Method B): 1.81 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 11.07 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.1 Hz,1H), 8.12 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.82 (dd, J=5.6, 2.2 Hz, 1H),7.67 (s, 1H), 7.41 (dd, J=9.2, 1.0 Hz, 2H), 7.36 (ddd, J=8.5, 2.4, 1.2Hz, 1H), 7.25-7.18 (m, 2H), 7.07 (d, J=2.3 Hz, 1H) ppm.

Example 1675-[[2-(4-Fluoro-2-methoxy-phenoxy)-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(159)

This compound was made in an analogous fashion to Example 92 exceptemploying 4-fluoro-2-methoxy-phenol in the fluorine-displacement step(Step 2). The yield of the desired product after purification was 38.7mg (58%). ESI-MS m/z calc. 517.09, found 518.2 (M+1)+; retention time(Method B): 1.66 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ11.35 (s, 1H), 8.84 (dd, J=2.5, 0.7 Hz, 1H), 8.28 (dd, J=8.6, 2.5 Hz,1H), 8.10-8.05 (m, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.94 (s, 1H), 7.60 (s,1H), 7.28 (dd, J=8.9, 5.8 Hz, 1H), 7.22-7.15 (m, 2H), 6.88 (ddd, J=8.8,8.1, 2.9 Hz, 1H), 3.77 (s, 3H) ppm.

Example 1685-Benzyloxy-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(217)

Step 1: 2-Bromo-4-fluoro-5-(trifluoromethyl)phenol

To a mixture of 4-fluoro-3-(trifluoromethyl)phenol (10 g, 55.5 mmol) inacetic acid (50 mL) was added bromine (2.9 mL, 55.5 mmol) and themixture was stirred at room temperature overnight. Additional bromine(1.4 mL, 27.8 mmol) was added and the reaction mixture was heated at 80°C. for 4 hours. The reaction mixture was diluted with water (10 mL) anddiethyl ether (300 mL). The aqueous portion was carefully neutralizedwith saturated aqueous sodium bicarbonate solution and extracted withdichloromethane (3×50 mL). The organic portions were combined, driedover Na₂SO₄, filtered and concentrated in vacuo. Product was purified bysilica gel chromatography (0-100% ethyl acetate/petroleum ether) toprovide 2-bromo-4-fluoro-5-(trifluoromethyl)phenol (2.4 g, 17%). ESI-MSm/z calc. 257.93, found 259.1 (M+1)+; retention time (Method B): 1.48minutes (3 minutes run).

Step 2: 1-Benzyloxy-2-bromo-4-fluoro-5-(trifluoromethyl)benzene

A mixture of 2-bromo-4-fluoro-5-(trifluoromethyl)phenol (1.5 g, 5.79mmol) and potassium carbonate (2.40 g, 17.4 mmol) in DMF (15 mL) wasstirred at room temperature for 5 minutes. Bromomethylbenzene (1.29 g,7.53 mmol) was added slowly under an atmosphere of nitrogen and wasstirred at room temperature for 3 hours. The reaction mixture wasquenched with water and the precipitated solid was filtered. The solidwas washed with water, taken up in DCM, dried over MgSO₄, filtered andconcentrated in vacuo. The product was purified by silica gelchromatography (0-10% ethyl acetate/petroleum ether) to provide1-benzyloxy-2-bromo-4-fluoro-5-(trifluoromethyl)benzene (1.26 g, 62%).ESI-MS m/z calc. 347.98, found 350.0 (M+1)+; retention time (Method A):0.84 minutes (1 minute run).

Step 3: 3-Benzyloxy-2-bromo-6-fluoro-5-(trifluoromethyl)benzoic Acid

To a solution of 1-benzyloxy-2-bromo-4-fluoro-5-(trifluoromethyl)benzene(500 mg, 1.43 mmol) in THF (5 mL) was added LDA dropwise (800 μL of 2 M,1.6 mmol) while maintaining the temperature below −70° C. and thereaction mixture was stirred at −70° C. for 1 hour. Carbon dioxide (dryice) was bubbled through the reaction mixture maintaining thetemperature below −70° C. The reaction mixture was allowed to warm toroom temperature then quenched with saturated ammonium chloridesolution. 1 N NaOH was added to make the reaction mixture basic and theaqueous layer was extracted by diethyl ether. The aqueous layer wasacidified with 6 N HCl and extracted with DCM, dried over MgSO₄,filtered and concentrated in vacuo to provide3-benzyloxy-2-bromo-6-fluoro-5-(trifluoromethyl)benzoic acid (262 mg,44%). The product was used crude in next step. ESI-MS m/z calc. 391.97,found 394.9 (M+1)+; retention time (Method B): 1.7 minutes (3 minutesrun). ¹H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 7.60 (d, J=6.3 Hz, 1H),7.53-7.47 (m, 2H), 7.46-7.40 (m, 2H), 7.39-7.33 (m, 1H), 5.35 (s, 2H)ppm.

Step 4:5-Benzyloxy-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicAcid

To a mixture of 3-benzyloxy-2-bromo-6-fluoro-5-(trifluoromethyl)benzoicacid (100 mg, 0.25 mmol), 4-(trifluoromethoxy)phenol (40 μL, 0.31 mmol)and cesium carbonate (110 mg, 0.34 mmol) in toluene (1 mL) was addedcopper (I) iodide (30 mg, 0.16 mmol). The vial was sealed and heated at100° C. with vigorous stirring for 4 hours. After cooling to roomtemperature the mixture was acidified with HCl, filtered and the aqueouslayer was extracted with DCM. The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. Product waspurified by silica gel column chromatography (0-30% ethylacetate/hexanes) to provide5-benzyloxy-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (45 mg, 36%). ESI-MS m/z calc. 490.07, found 491.1 (M+1)+;retention time (Method B): 2.05 minutes (3 minutes run). ¹H NMR (400MHz, DMSO-d6) δ 7.70 (d, J=6.7 Hz, 1H), 7.35-7.30 (m, 2H), 7.28-7.16 (m,3H), 7.06-7.00 (m, 2H), 6.96-6.90 (m, 2H), 5.14 (s, 2H) ppm.

Step 5:5-Benzyloxy-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(217)

A mixture of5-benzyloxy-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (40 mg, 0.082 mmol), 5-amino-2-fluoro-benzamide (14 mg, 0.09 mmol),HATU (38 mg, 0.10 mmol) and DIPEA (50 μL, 0.2871 mmol) in DMF (700 μL)was stirred at room temperature for 3 hours. The reaction mixture wasquenched with water and the precipitated solid was filtered and washedwith water. The solid was taken up in DCM, dried over MgSO₄, filteredand concentrated in vacuo. Product was purified by silica gelchromatography (0-50% ethyl acetate/hexanes) to afford5-benzyloxy-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(28 mg, 52%). ESI-MS m/z calc. 626.11, found 627.2 (M+1)+; retentiontime (Method B): 2.09 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 11.01 (s, 1H), 7.89 (dd, J=6.4, 2.8 Hz, 1H), 7.74 (d, J=6.7 Hz, 1H),7.71-7.63 (m, 3H), 7.36-7.18 (m, 6H), 7.09-7.04 (m, 2H), 6.97-6.92 (m,2H), 5.17 (s, 2H) ppm.

Example 1694-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(218)

Step 1:1-Bromo-3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)benzene

A mixture of 6-bromo-2-fluoro-3-(trifluoromethoxy)phenol (20 g, 72.7mmol), potassium carbonate (13.1 g, 94.8 mmol) andtrideuterio(iodo)methane (14.2 g, 98.0 mmol) in DMF (120 mL) was stirredat room temperature for 2 hours. The reaction mixture was diluted withMTBE (120 mL) and water (120 mL). The aqeuous layer was furtherextracted with MTBE (50 mL). Combined organic fractions were washed withbrine (50 mL), dried over MgSO₄, filtered and concentrated in vacuo toprovide1-bromo-3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)benzene(20.5 g, 97%). The product was used crude in the next step. ¹H NMR (500MHz, CDCl₃) δ 7.36 (dd, J=9.0, 2.4 Hz, 1H), 6.97 (ddq, J=9.7, 7.2, 1.3Hz, 1H) ppm.

Step 2: 3-Fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol

To a mixture of1-bromo-3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)benzene(19.3 g, 66.1 mmol) and Pd₂(dba₃) (3.02 g, 3.30 mmol) in dioxane (100mL) was added ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane(2.92 g, 6.88 mmol) and potassium hydroxide (11.1 g, 198 mmol) in water(50 mL). The mixture was stirred at 100° C. for 2 hours. The reactionmixture was diluted with water (200 mL) and MTBE (200 mL). The aqueouslayer was further extracted with MTBE (200 mL). The aqueous layer wasacidified with 2 N HCl (200 mL) and extracted with MTBE. The organiclayer was washed with brine (300 mL), dried over MgSO₄, filtered andconcentrated in vacuo to provide3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (15.9 g,105%) as an orange liquid. ¹H NMR (500 MHz, CDCl₃) δ 6.92 (ddq, J=9.1,7.9, 1.2 Hz, 1H), 6.72 (dd, J=9.1, 2.2 Hz, 1H), 5.87 (s, 1H) ppm.

Step 3: Methyl4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of 2,6-difluoro-3-(trifluoromethyl)benzoicacid (1 g, 3.1 mmol) in DCM (17 mL) was added DMF (24 μL, 0.31 mmol) anddropwise oxalyl chloride (810 μL, 9.29 mmol) and was stirred for 2hours. The reaction mixture was concentrated in vacuo to afford the acidchloride as a pale yellow oil. A solution of the acid chloride residuein DCM (17 mL) was added dropwise to an ice-cooled mixture of methyl4-aminopyridine-2-carboxylate (HCl salt) (820 mg, 4.35 mmol) andtriethylamine (2.6 mL, 18.7 mmol) in DCM (17 mL). The mixture wasstirred and warmed to room temperature overnight. The reaction mixturewas quenched with water (10 mL) and extracted with DCM (2×10 mL). Thecombined organics were dried by phase separation cartridge andconcentrated in vacuo. The product was purified by silica gelchromatography (ethyl acetate/petroleum ether) to provide methyl4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(700 mg, 63%). ESI-MS m/z calc. 360.05, found 361.0 (M+1)+, 359.9(M−1)−; retention time (Method F): 0.83 minutes (1.5 minutes run). ¹HNMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.72 (dd, J=5.4, 0.6 Hz, 1H),8.42 (dd, J=2.1, 0.6 Hz, 1H), 8.20-8.09 (m, 1H), 7.90 (dd, J=5.4, 2.2Hz, 1H), 7.66-7.56 (m, 1H), 3.95 (s, 3H) ppm.

Step 4: Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A mixture of methyl4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(430 mg, 1.19 mmol), cesium carbonate (778 mg, 2.39 mmol) and3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (553 mg, 2.15mmol) in acetonitrile (3 mL) was heated in the microwave at 90° C. for 1hour. The cooled reaction mixture was diluted with ethyl acetate (30 mL)and water (30 mL). The aqeuous layer was further extracted with ethylacetate (10 mL). Combined organic portions were washed with brine (20mL), dried over MgSO₄ and concentrated in vacuo to provide methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(430 mg, 59%). The product was used crude in the next step. ESI-MS m/zcalc. 569.09, found 570.0 (M+1)+; retention time (Method F): 1.06minutes (1.5 minutes run).

Step 5:4-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(218)

To methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(900 mg, 0.9800 mmol) was added ammonia (5 mL of 7 M in methanol, 35mmol) followed by methanol (5 mL) and the mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo.The product was purified by HPLC (0-100% acetonitrile/water/0.1%ammonium hydroxide) to provide4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(345 mg, 62%) as a white solid. ESI-MS m/z calc. 554.09, found 555.1(M+1)+; retention time (Method E): 3.38 minutes (5 minutes run). ¹H NMR(500 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.33 (d,J=2.2 Hz, 1H), 8.10 (s, 1H), 7.90-7.80 (m, 2H), 7.66 (s, 1H), 7.40 (t,J=8.5 Hz, 1H), 7.23 (dd, J=9.8, 1.9 Hz, 1H), 6.92 (d, J=8.9 Hz, 1H) ppm.

Example 1704-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(228)

A mixture of methylamine (2.83 mL of 2 M, 5.67 mmol) and methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(prepared as described in Example 169, step 4, 100 mg, 0.176 mmol) wasstirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo and purified by HPLC (37-100%acetonitrile/water/0.1% ammonium hydroxide) to provide4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(13 mg, 12%). ESI-MS m/z calc. 568.11, found 569.2 (M+1)+; 567.4 (M−1)−;Retention time (Method E): 3.49 minutes (5 minutes run). ¹H NMR (500MHz, DMSO-d6) δ 11.50 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 8.56 (dd, J=9.0,5.4 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 7.90-7.83 (m, 2H), 7.40 (t, J=8.7Hz, 1H), 7.23 (dd, J=9.3, 2.0 Hz, 1H), 6.92 (d, J=8.9 Hz, 1H), 2.82 (d,J=4.8 Hz, 3H) ppm.

Example 171N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(219)

Step 1: 1-Bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene

To a solution of 6-bromo-2-fluoro-3-(trifluoromethoxy)phenol (5 g, 18.18mmol) in DMF (30 mL) was added potassium carbonate (3.27 g, 23.66 mmol)followed by iodomethane (1.47 mL, 23.61 mmol). The mixture was stirredat room temperature for 2.5 hours then partitioned between ethyl acetate(50 mL) and water (50 mL); the organics were collected and the aqueousfurther extracted with ethyl acetate (2×50 mL). The organics werecombined, washed with water (3×50 mL), brine (50 mL), dried over MgSO₄,filtered and concentrated in vacuo to provide1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene (4.6 g, 88%) asan orange oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.61 (dd, J=9.1, 2.3 Hz, 1H),7.31 (ddq, J=8.9, 7.6, 1.3 Hz, 1H), 3.95 (d, J=1.6 Hz, 3H) ppm.

Step 2: 3-Fluoro-2-methoxy-4-(trifluoromethoxy)phenol

To a solution of 1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene(17.3 g, 59.86 mmol) in dioxane (78 mL) was added(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (2.74 g, 2.99 mmol),ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (2.54 g, 5.99mmol) and potassium hydroxide (10.1 g, 180.1 mmol) followed by water (39mL). The dark red suspension was heated to reflux for 1.25 hours. Thereaction mixture was cooled down to room temperature. The reactionmixture was partitioned between MTBE (170 mL) and water (85 mL). Thesolid was filtered and rinsed with more MTBE and water. The aqueouslayer was acidified to pH 1 by addition of HCl (61 mL of 2 M, 122 mmol)then extracted twice with MTBE (50 mL). The combined organic phases werewashed with brine (1×20 mL), dried over MgSO₄, filtered and concentratedin vacuo to provide 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (14.1g, 89%) as an orange oil. ESI-MS m/z calc. 226.03, found 225.0 (M−1)−;retention time (Method F): 0.79 minutes (1.5 minutes run). ¹H NMR (400MHz, DMSO-d6) δ 10.17 (d, J=1.1 Hz, 1H), 7.07 (dddd, J=9.6, 8.4, 2.4,1.2 Hz, 1H), 6.73 (dd, J=9.2, 2.2 Hz, 1H), 3.83 (d, J=0.6 Hz, 3H) ppm.

Step 3:N-(3-Carbamoyl-4-fluoro-phenyl)-2,6-difluoro-3-(trifluoromethyl)benzamide

A solution of 2,6-difluoro-3-(trifluoromethyl)benzoic acid (300 mg, 1.33mmol) in DCM (6 mL) was cooled using an ice-bath. To this was added DMF(10 μL, 0.13 mmol) followed by careful addition of oxalyl chloride (350μL, 4.012 mmol). The solution was stirred with an ice-bath in place for2 hours. This solution was concentrated in vacuo and azeotroped with DCMto afford the acid chloride as a cream colored solid. This acid chloridewas taken up in DCM (3 mL) and added to an ice-bath cooled solution of5-amino-2-fluoro-benzamide (208 mg, 1.35 mmol) and DIPEA (700 μL, 4.019mmol) in DCM (3 mL). The resulting cream suspension was stirred withice-bath in place for 1 hour and then at room temperature for 18 hours.DCM was removed in vacuo and partitioned with ethyl acetate and water.Layers were separated by phase separation cartridge and the organiclayer was concentrated in vacuo to affordN-(3-carbamoyl-4-fluoro-phenyl)-2,6-difluoro-3-(trifluoromethyl)benzamide(489 mg, 95%) as a cream solid. ESI-MS m/z calc. 362.05, found 363.0(M+1)+; retention time (Method F): 0.79 minutes (1.5 minutes run). ¹HNMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.11-8.02 (m, 1H), 7.98 (dd,J=6.4, 2.8 Hz, 1H), 7.82-7.76 (m, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.53(t, J=8.6 Hz, 1H), 7.33 (dd, J=10.1, 9.0 Hz, 1H) ppm.

Step 4:N-(3-Carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(219)

In a microwave vial was combinedN-(3-carbamoyl-4-fluoro-phenyl)-2,6-difluoro-3-(trifluoromethyl)benzamide(100 mg, 0.26 mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (120mg, 0.265 mmol) and cesium carbonate (125 mg, 0.384 mmol) inacetonitrile (4 mL). The resulting suspension was heated in themicrowave at 90° C. μW for 60 minutes then the mixture was concentratedin vacuo and partitioned with ethyl acetate and water. The layers wereseparated and the organic phase passed through a phase separationcartridge before concentrating in vacuo and purifying by HPLC (37-100%acetonitrile/water/0.1% ammonium hydroxide) to provideN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(18 mg, 12%) as a white solid. ESI-MS m/z calc. 568.07, found 569.0(M+1)+; 567.0 (M−1)−; Retention time (Method E): 3.38 minutes (5 minutesrun). ¹H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.99 (dd, J=6.4, 2.8Hz, 1H), 7.84 (t, J=8.6 Hz, 1H), 7.77 (ddd, J=8.9, 4.3, 2.8 Hz, 1H),7.72 (s, 1H), 7.68 (s, 1H), 7.41 (dd, J=9.3, 7.9 Hz, 1H), 7.30 (dd,J=10.0, 8.9 Hz, 1H), 7.21 (dd, J=9.3, 2.1 Hz, 1H), 6.90 (d, J=8.9 Hz,1H), 3.87 (s, 3H) ppm.

Example 1724-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(232)

Step 1:1-Bromo-3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)benzene

LDA (6.5 mL of 2 M, 13 mmol) was added dropwise to a solution of4-bromo-2-fluoro-1-(trifluoromethoxy)benzene (3.03 g, 11.7 mmol) in THF(35 mL) at −78° C. The reaction was stirred at this temperature for 30minutes then trideuterio(iodo)methane (1.14 mL, 17.9 mmol) was added.The mixture was stirred at −78° C. for 30 minutes then allowed to warmto ambient temperature and stirred for 30 minutes. The reaction wasquenched by the addition of aqueous NH₄Cl and the mixture was extractedwith ethyl acetate (×3). The combined organic extracts were dried overMgSO₄, filtered and concentrated in vacuo to afford1-bromo-3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)benzene (3.23mg). The product was used crude in the next step.

Step 2: 3-Fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)phenol

To a solution of1-bromo-3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)benzene (3.23g, 11.7 mmol) in dioxane (17 mL) was added Pd₂(dba₃) (546 mg, 0.60 mmol)followed by di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane(522 mg, 1.23 mmol) and potassium hydroxide (1.97 g, 35.1 mmol) in water(10 mL). The mixture was stirred at 100° C. for 2 hours. The reactionmixture was separated between water (200 mL) and MTBE (200 mL). Theaqueous layer was further washed with MTBE (200 mL). The aqueous layerwas acidified with 2N HCl (200 mL) and extracted with MTBE. The organiclayer was further washed with brine (300 mL) then dried over MgSO₄,filtered and concentrated in vacuo to provide3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)phenol (631 mg, 25%)as an orange liquid. ESI-MS m/z calc. 213.05, found 212.0 (M−1)−;retention time (Method F): 0.90 minutes (1.5 minutes run). ¹H NMR (500MHz, CDCl₃) δ 7.01 (t, J=8.7 Hz, 1H), 6.55 (d, J=8.9, 1.9 Hz, 1H) ppm.

Step 3: Methyl4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of 2,6-difluoro-3-(trifluoromethyl)benzoicacid (1 g, 3.1 mmol) in DCM (17 mL) was added DMF (24 μL, 0.31 mmol) andoxalyl chloride (810 μL, 9.285 mmol) dropwise and the mixture stirredfor 2 hours. The reaction mixture was concentrated in vacuo to affordthe acid chloride as a pale yellow oil. A solution of the residue in DCM(17 mL) was added dropwise to an ice-cooled mixture of methyl4-aminopyridine-2-carboxylate (HCl salt) (820 mg, 4.348 mmol) andtriethylamine (2.6 mL, 18.65 mmol) in DCM (17 mL). The resulting mixturewas stirred and warmed to room temperature overnight. The reactionmixture was quenched with water (10 mL) and extracted with DCM (2×10mL). The combined organics were dried by phase separation cartridge,concentrated in vacuo and purified by column chromatography (ethylacetate/petroleum ether), to afford methyl4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(700 mg, 63%) as a white solid. ESI-MS m/z calc. 360.05, found 361.0(M+1)+; 359.9 (M−1)−; retention time (Method F): 0.83 minutes (1.5minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.72 (dd,J=5.4, 0.6 Hz, 1H), 8.42 (dd, J=2.1, 0.6 Hz, 1H), 8.20-8.09 (m, 1H),7.90 (dd, J=5.4, 2.2 Hz, 1H), 7.66-7.56 (m, 1H), 3.95 (s, 3H) ppm.

Step 4: Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

Methyl4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(353 mg, 0.98 mmol),3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)phenol (200 mg, 0.94mmol) and Cs₂CO₃ (500 mg, 1.54 mmol) were combined in DMF (4 mL) andstirred overnight at 70° C. The reaction mixture was partitioned betweenethyl acetate and brine. The organic layer was washed with brine, driedover MgSO₄, filtered and evaporated. The product was purified by HPLC(37-100% acetonitrile/water/0.1% ammonium hydroxide) to provide methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(180 mg, 33%). ESI-MS m/z calc. 553.10, found 554.2 (M+1)+; retentiontime (Method F): 1.06 minutes (1.5 minutes run). ¹H NMR (500 MHz, CDCl₃)δ 8.83 (s, 1H), 8.65 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H),8.11-8.00 (m, 1H), 7.59 (t, J=8.3 Hz, 1H), 7.26-7.16 (m, 1H), 6.86 (dd,J=9.0, 1.9 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H), 3.94 (s, 3H) ppm.

Step 5:4-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(232)

A solution of methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(160 mg, 0.29 mmol) and ammonia (8 mL of 7 M in methanol, 56 mmol) wasstirred at room temperature for 24 hours. The reaction mixture wasconcentrated in vacuo to provide4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethyl)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(154 mg, 92%). ESI-MS m/z calc. 538.10, found 539.1 (M+1)+; retentiontime (Method E): 3.44 minutes (5 minutes run). ¹H NMR (500 MHz, DMSO-d6)δ 11.48 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.09(d, J=2.8 Hz, 1H), 7.87 (t, J=8.6 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H),7.65 (d, J=2.9 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H), 7.13 (dd, J=9.1, 1.8 Hz,1H), 6.89 (d, J=8.9 Hz, 1H) ppm.

Example 1735-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(221)

Step 1: Methyl5-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of 2,6-difluoro-3-(trifluoromethyl)benzoicacid (300 mg, 0.9288 mmol) in DCM (5 mL) was added DMF (7.2 μL, 0.093mmol) and dropwise oxalyl chloride (245 μL, 2.81 mmol) and the mixturewas stirred for 2 hours. The reaction mixture was concentrated in vacuoto afford the acid chloride as a colourless waxy solid. A solution ofthe acid chloride residue in DCM (5 mL) was added to methyl5-aminopyridine-2-carboxylate (198 mg, 1.30 mmol) and triethylamine (780μL, 5.60 mmol) in an ice bath. The resulting mixture was stirred andwarmed to room temperature over 2 hours. The reaction mixture wasquenched with water (10 m) and extracted with DCM (2×10 mL). Thecombined organics were dried by phase separation cartridge andconcentrated in vacuo to afford a brown waxy solid. This was purified bysilica gel chromatography (0-100% ethyl acetate/petroleum ether) toafford methyl5-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(225 mg, 67%) as an off-white gummy solid. ESI-MS m/z calc. 360.05,found 361.0 (M+1)+; 359.0 (M−1)−; retention time (Method F): 0.83minutes (1.5 minutes run). H NMR (400 MHz, CDCl₃) δ 10.35 (s, 1H), 8.75(d, J=2.5 Hz, 1H), 8.44 (dd, J=8.6, 2.4 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H),7.53 (td, J=8.3, 5.9 Hz, 1H), 6.96-6.87 (m, 1H), 3.84 (s, 3H) ppm.

Step 2: Methyl5-[[2-fluoro-6-[3-difluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

Methyl5-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(200 mg, 0.56 mmol), cesium carbonate (283 mg, 0.87 mmol) and3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (prepared asdescribed in Example 169, step 2, 134 mg, 0.58 mmol) were combined inDMF (5 mL) and stirred over the weekend at 30° C. The reaction mixturewas cooled and purified by HPLC (37-100% acetonitrile/water/0.1%ammonium hydroxide) to provide methyl5-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(98 mg, 31%). ESI-MS m/z calc. 569.09, found 570.0 (M+1)+; 568.1 (M−1)−;retention time (Method F): 1.07 minutes (1.5 minutes run). ¹H NMR (400MHz, CDCl₃) δ 8.69 (dd, J=2.6, 0.7 Hz, 1H), 8.57 (dd, J=8.6, 2.6 Hz,1H), 8.49 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 7.64 (t, J=8.3 Hz, 1H),7.19-7.09 (m, 1H), 7.06 (dd, J=9.2, 2.1 Hz, 1H), 6.67 (d, J=8.9 Hz, 1H),4.02 (s, 3H) ppm.

Step 3:5-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(221)

Methyl5-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(98 mg, 0.17 mmol) was dissolved in ammonia (5 mL of 7 M in methanol, 35mmol) and stirred at ambient temperature for 3 days. The reactionmixture was concentrated in vacuo to afford5-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(94 mg, 81%). ESI-MS m/z calc. 554.09, found 554.9 (M+1)+; 552.7 (M−1)−;retention time (Method E): 3.28 minutes (5 minutes run). ¹H NMR (400MHz, CDCl₃) δ 9.13 (s, 1H), 8.71 (d, J=2.5 Hz, 1H), 8.22 (dd, J=8.6, 2.5Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.67-7.61 (m, 1H), 7.48 (t, J=8.3 Hz,1H), 7.07-6.89 (m, 2H), 6.53 (d, J=8.8 Hz, 1H), 5.73 (s, 1H) ppm.

Example 1745-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(229)

A mixture of methylamine (3.6 mL of 2 M in methanol, 7.20 mmol) andmethyl5-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(prepared as described in Example 173, step 2, 126 mg, 0.222 mmol) wasstirred at room temperature overnight. The reaction mixture was thenconcentrated in vacuo and purified by HPLC (37-100%acetonitrile/water/0.1% ammonium hydroxide) to deliver5-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(11 mg, 8%). ESI-MS m/z calc. 568.11, found 569.2 (M+1)+; 567.3 (M−1)−;retention time (Method E): 3.43 minutes (5 minutes run). ¹H NMR (500MHz, DMSO-d6) δ 11.45 (s, 1H), 8.88 (d, J=2.4 Hz, 1H), 8.66 (q, J=5.0Hz, 1H), 8.29 (dd, J=8.6, 2.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.87 (t,J=8.6 Hz, 1H), 7.40 (tt, J=9.2, 1.3 Hz, 1H), 7.23 (dd, J=9.3, 2.1 Hz,1H), 6.93 (d, J=8.9 Hz, 1H), 2.82 (d, J=4.8 Hz, 3H) ppm.

Example 1754-[[6-[3-Fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(226)4-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(227)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-2,6-difluoro-3-(trifluoromethyl)benzamide

To an ice-cooled solution of 2,6-difluoro-3-(trifluoromethyl)benzoicacid (1 g, 3.1 mmol) in DCM (15 mL) was added DMF (25 μL, 0.32 mmol)followed by dropwise addition of oxalyl chloride (810 μL, 9.29 mmol) andwas stirred for 2 hours. The reaction mixture was concentrated in vacuoto afford the acid chloride as a pale yellow oil. To a solution of theacid chloride residue in DCM (15 mL) in an ice bath was added2-bromo-5-methyl-pyridin-4-amine (HCl salt) (970 mg, 4.34 mmol) followedby triethylamine (2.6 mL, 18.65 mmol). The resulting mixture was stirredand warmed to room temperature over 2 hours. Reaction mixture wasquenched with water (10 mL) and extracted with DCM (2×10 mL). Thecombined organics were dried by phase separation cartridge andconcentrated in vacuo to afford a brown waxy solid. The product waspurified by silica gel chromatography (0-100% ethyl acetate/hexanes) andtriturated with DCM to provideN-(2-bromo-5-methyl-4-pyridyl)-2,6-difluoro-3-(trifluoromethyl)benzamide(320 mg, 26%). ESI-MS m/z calc. 393.97, found 395.0 (M+1)+; 393.0(M−1)−; retention time (Method F): 0.91 minutes (1.5 minutes run). ¹HNMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.32-8.26 (m, 1H), 8.13-8.03 (m,2H), 7.54 (t, J=8.7 Hz, 1H), 2.25-2.16 (m, 3H) ppm.

Step 2:N-(2-Bromo-5-methyl-4-pyridyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide

N-(2-Bromo-5-methyl-4-pyridyl)-2,6-difluoro-3-(trifluoromethyl)benzamide(320 mg, 0.81 mmol), cesium carbonate (415 mg, 1.274 mmol) and3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (prepared asdescribed in Example 169, step 2, 196 mg, 0.86 mmol) were combined inDMF (4.8 mL) and stirred for 10 days at 30° C., then 40° C. for afurther 4 days. The mixture was purified by HPLC (37-100%acetonitrile/water/0.1% ammonium hydroxide) and freeze dried to provideN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(157 mg, 32%). ESI-MS m/z calc. 604.26, found 606.0 (M+1)+; 603.9(M−1)−; retention time (Method F): 1.10 minutes (1.5 minutes run). ¹HNMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.85(t, J=8.6 Hz, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.21 (d, J=9.1 Hz, 1H), 6.91(d, J=8.9 Hz, 1H), 2.21 (s, 3H) ppm.

Step 3: Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(157 mg, 0.26 mmol) was dissolved in methanol (7.4 mL) and triethylamine(57 mg, 0.56 mmol) and Pd(dppf)Cl₂.DCM (50 mg, 0.06 mmol) were added.Carbon monoxide was bubbled through the reaction mixture for 5 minuteswhilst being vigorously stirred at ambient temperature. The reactionmixture was sealed and heated to 75° C. for 18 hours, then cooled toroom temperature before concentrating in vacuo. The product was purifiedby HPLC (37-100% acetonitrile/water/0.1% ammonium hydroxide) to providemethyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(86 mg, 57%) as a white solid. ESI-MS m/z calc. 583.11, found 584.2(M+1)+; retention time (Method F): 1.06 minutes (1.5 minutes run). ¹HNMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.60-8.49 (m, 2H), 7.87 (t,J=8.6 Hz, 1H), 7.42 (ddd, J=9.4, 8.1, 1.4 Hz, 1H), 7.22 (dd, J=9.3, 2.1Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 2.33 (s, 3H) ppm.

Step 4:4-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(227) &4-[[6-[3-Fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(226)

Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(86 mg, 0.15 mmol) was dissolved in ammonia (4 mL of 7 M in methanol, 28mmol) and stirred at 40° C. over the weekend. Additional ammonia (2 mLof 7 M in methanol, 14 mmol) was added and the mixture was heated to 60°C. in a sealed tube for a further 24 hours. The reaction mixture wasconcentrated in vacuo and purified by SFC ((R,R)-Whelk-O1 column, 80%CO2/20% methanol with 20 mM ammonia) to afford:4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(227, 30 mg, 36%). ESI-MS m/z calc. 568.11, found 569.2 (M+1)+; 567.1(M−1)−; retention time (Method E): 3.37 minutes (5 minutes run). ¹H NMR(400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.41 (s, 1H), 7.60 (t, J=8.4 Hz, 1H),7.15-7.05 (m, 1H), 7.03 (dd, J=9.2, 2.0 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H),2.36 (s, 3H) ppm, and4-[[6-[3-Fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(226.16 mg, 19%). ESI-MS m/z calc. 580.13, found 581.2 (M+1)+; 579.1;retention time (Method E): 3.39 minutes (5 minutes run). ¹H NMR (400MHz, CD₃OD) δ 8.60 (s, 1H), 8.38 (t, J=0.8 Hz, 1H), 7.57 (d, J=8.9 Hz,1H), 7.07 (ddq, J=8.9, 7.6, 1.2 Hz, 1H), 6.98 (dd, J=9.2, 2.1 Hz, 1H),6.55 (d, J=8.8 Hz, 1H), 4.01 (s, 3H), 2.34 (s, 3H) ppm.

Example 1764-[[3-Chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(220)

Step 1: Methyl4-[(6-bromo-3-chloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate

To an ice-cooled solution of 6-bromo-3-chloro-2-fluoro-benzoic acid(1.08 g, 4.27 mmol) in DCM (38 mL) was added DMF (89 μL, 1.15 mmol)followed by dropwise addition of oxalyl chloride (1.15 mL, 13.16 mmol)and was stirred for 1 hour. The reaction mixture was concentrated invacuo to afford the acid chloride as a white solid. A solution of theacid chloride residue in DCM (38 mL) was then added dropwise to an icebath cooled solution of methyl 4-aminopyridine-2-carboxylate (714 mg,4.69 mmol) and N-ethyl-N-isopropyl-propan-2-amine (4.5 mL, 25.84 mmol).The resulting mixture was stirred at room temperature for 3 hours. Thesolvent was evaporated and the residue was separated between 2 N NaOHand ethyl acetate. The organic layer was washed with 1 M citric acid,then brine, dried over MgSO₄, filtered and evaporated to provide a cruderesidue, which was purified by HPLC (26-100% acetonitrile/0.1% ammoniumhydroxide) to provide methyl4-[(6-bromo-3-chloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (256mg, 15%) as a white solid. ¹H NMR (500 MHz, DMSO-d6) δ 8.67 (dd, J=5.4,0.6 Hz, 1H), 8.40 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.4, 2.1 Hz, 1H), 7.76(dd, J=8.7, 7.8 Hz, 1H), 7.69 (dd, J=8.7, 1.2 Hz, 1H), 3.90 (s, 3H) ppm.

Step 2: Methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

To a mixture of3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (165 mg, 0.72mmol), methyl4-[(6-bromo-3-chloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (256mg, 0.66 mmol) and cesium carbonate (510 mg, 1.565 mmol) in toluene (5mL) was added copper (I) iodide (45 mg, 0.23 mmol) and the resultingmixture was heated at 100° C. for 4 hours. The mixture was cooled toroom temperature and partitioned between 1 M citric acid and ethylacetate. The organics were washed with water (20 mL), brine (2×20 mL),dried over MgSO₄ and concentrated. The crude product was purified byHPLC (37-100% acetonitrile/0.1% ammonium hydroxide) to afford methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(38 mg, 10%). ESI-MS m/z calc. 535.06, found 535.9 (M+1)+; Retentiontime (Method F): 1.02 minutes (1.5 minutes run).

Step 3:4-[[3-Chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(220)

A solution of methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(37 mg, 0.07 mmol) and ammonia (2 mL of 7 M in methanol, 14.00 mmol) wasstirred at room temperature for 24 hours. The reaction mixture wasconcentrated in vacuo to provide4-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(35 mg, 92%). ESI-MS m/z calc. 520.07, found 521.2 (M+1)+; Retentiontime (Method E): 3.34 minutes (5 minutes run). ¹H NMR (500 MHz, CDCl₃) δ9.72 (br s, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.16(br s, 1H), 7.88 (br s, 1H), 7.43 (t, J=8.4 Hz, 1H), 7.04 (t, J=8.3 Hz,1H), 7.00-6.94 (m, 1H), 6.59 (d, J=8.9 Hz, 1H), 5.33 (d, J=15.0 Hz, 1H)ppm.

Example 1774-[[4-Chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoyl]amino]pyridine-2-carboxamide(222)

Step 1: Methyl 4-chloro-2,6-difluoro-benzoate

Iodomethane (1.49 mL, 23.93 mmol) was added to a stirred suspension of4-chloro-2,6-difluoro-benzoic acid (4 g, 20.77 mmol) and cesiumcarbonate (7.45 g, 22.87 mmol) in DMF (40 mL) and the reaction mixturewas stirred at ambient temperature for 18 hours. The mixture waspartitioned between water and diethyl ether. The aqueous layer wasfurther extracted with diethyl ether (×2) and the combined organiclayers were washed with brine, dried over MgSO₄, filtered and evaporatedto give methyl 4-chloro-2,6-difluoro-benzoate (4.33 g, 100%). ¹H NMR(500 MHz, DMSO-d6) δ 7.59-7.53 (m, 2H), 3.90 (s, 3H) ppm.

Step 2: Methyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate

A mixture of cesium carbonate (6.4 g, 19.64 mmol),3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (3.11 g,13.57 mmol) and methyl 4-chloro-2,6-difluoro-benzoate (2.67 g, 12.92mmol) in DMF (50 mL) was stirred at ambient temperature for 2 hours,then at 70° C. for 16 hours. The reaction was diluted with ethyl acetateand washed with water (×3) and brine (×2). The organic layer was driedover MgSO₄, filtered and concentrated in vacuo to afford methyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(4.88 g, 91%) as a yellow oil. ESI-MS m/z calc. 415.03, found 416.0(M+1)+; Retention time (Method F): 1.14 minutes (1.5 minutes run).

Step 3: Methyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoate

LDA (340 μL of 2 M solution in THF, 0.68 mmol) was added dropwise to asolution of methyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(258 mg, 0.62 mmol) in THF (3 mL) at −78° C. The reaction was stirred atthis temperature for 10 minutes then trideuterio(iodo)methane (60 μL,0.94 mmol) was added. The mixture was stirred at −78° C. for 30 minutesthen allowed to warm to room temperature. An additional portion of LDA(340 μL of 2 M, 0.68 mmol) was added at −78° C. and the mixture wasstirred for 10 minutes at this temperature. Additionaltrideuterio(iodo)methane (60 μL, 0.94 mmol) was then added and themixture was stirred at −78° C. for 30 minutes then allowed to warm toroom temperature and stirred for 30 minutes. The reaction was quenchedby the addition of water and the mixture was extracted with ethylacetate (×3). The combined organic extracts were dried over MgSO₄,filtered and concentrated in vacuo to afford methyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoate(277 mg, 100%). ¹H NMR (500 MHz, CDCl₃) δ 6.92 (ddt, J=7.9, 6.5, 1.3 Hz,1H), 6.73 (dd, J=9.2, 2.3 Hz, 1H), 6.53 (d, J=1.8 Hz, 1H), 3.81 (s, 3H)ppm.

Step 4:4-Chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoicAcid

To a slurry of methyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoate(277 mg, 0.64 mmol) in methanol (7 mL) and was added NaOH (3.1 mL of 2M, 6.2 mmol) and the reaction mixture was stirred for 24 hours at 50° C.The reaction was cooled to ambient temperature and the solvent wasremoved in vacuo. The residue was taken up in water and acidified with 2M HCl. The mixture was extracted with ethyl acetate (×3) and thecombined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to afford4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoicacid (310 mg, 100%) as a yellow solid. ESI-MS m/z calc. 418.05, found416.9 (M−1)−; Retention time (Method F): 0.76 minutes (1.5 minutes run).

Step 5: Methyl4-[[4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoicacid (300 mg, 0.71 mmol) in DCM (10 mL) was added DMF (15 μL, 0.19 mmol)followed by dropwise addition of oxalyl chloride (193 μL, 2.21 mmol).The reaction was stirred for 1 hour before concentrating in vacuo toafford the acid chloride. A solution of the acid chloride residue in DCM(10 mL) was then added dropwise to an ice-cooled solution of methyl4-aminopyridine-2-carboxylate (130 mg, 0.85 mmol) andN-ethyl-N-isopropyl-propan-2-amine (740 μL, 4.28 mmol). The resultingmixture was stirred at room temperature for 3 hours. The solvent wasevaporated and the residue was partitioned with 2 N NaOH and ethylacetate. The organic layer was washed with 1 M citric acid, brine, driedover MgSO₄, filtered and concentrated in vacuo to provide a cruderesidue, which was purified by HPLC (37-100% acetonitrile/0.1% ammoniumhydroxide) to provide methyl4-[[4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoyl]amino]pyridine-2-carboxylate(70 mg, 18%) as a white solid. ESI-MS m/z calc. 552.09, found 553.2(M+1)+; Retention time (Method F): 1.07 minutes (1.5 minute run).

Step 6:4-[[4-Chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoyl]amino]pyridine-2-carboxamide(222)

A solution of methyl4-[[4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoyl]amino]pyridine-2-carboxylate(70 mg, 0.126 mmol) and ammonia (4 mL of 7 M in methanol, 28.00 mmol)was stirred at room temperature for 24 hours. The reaction mixture wasconcentrated in vacuo to provide a crude material which was purified byHPLC (37-100% acetonitrile/0.1% ammonium hydroxide) to afford4-[[4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trideuteriomethyl)benzoyl]amino]pyridine-2-carboxamide(42 mg, 61%). ESI-MS m/z calc. 537.09, found 538.2 (M+1)+; Retentiontime (Method E): 3.38 minutes (5 minutes run). ¹H NMR (500 MHz, DMSO-d6)δ 11.32 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.08(d, J=2.9 Hz, 1H), 7.78 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (s, 1H), 7.32(ddd, J=9.4, 8.0, 1.2 Hz, 1H), 7.09-7.01 (m, 2H) ppm.

Example 1784-[[4-Chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoyl]amino]pyridine-2-carboxamide(233)

Step 1: Methyl4-chloro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-formyl-2-methoxy-benzoate

LDA (2.4 mL of 2 M, 4.80 mmol) was added dropwise to a solution ofmethyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(prepared as describe in Example 177, step 2 above, 11.33 g, 3.19 mmol)in THF (15 mL) at −78° C. The reaction was stirred at this temperaturefor 30 minutes then methyl formate (2 mL, 32.44 mmol) was added. Themixture was stirred at −78° C. for 30 minutes then allowed to warm toambient temperature over 30 minutes. The reaction was quenched by theaddition of water and extracted with ethyl acetate (×3). The combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo to afford methyl4-chloro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-formyl-2-methoxy-benzoate(1.60 g, 100%). ESI-MS m/z calc. 455.05, found 456.0 (M+1)+; Retentiontime (Method F): 1.05 minutes (1.5 minutes run).

Step 2: Methyl4-chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoate

Deoxo-fluor (3.55 g, 16.03 mmol) in DCM (7 mL) was added to a solutionof methyl4-chloro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-formyl-2-methoxy-benzoate(1.22 g, 2.68 mmol) in DCM (9 mL). The reaction mixture was stirred atroom temperature for 18 hours. The reaction was quenched by pouring ontoa saturated solution of NaHCO₃ then stirred for 30 minutes at roomtemperature. The layers were separated and the aqueous layer extractedwith DCM (×2). The organic extracts were combined and washed with waterthen brine to afford crude methyl4-chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoate(1.4 g, 110%) as an orange oil. ESI-MS m/z calc. 477.05, found 478.0(M+1)+; Retention time (Method F): 1.14 minutes (1.5 minutes run).

Step 3:4-Chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoicAcid

To a solution of methyl4-chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoate(1.28 g, 2.675 mmol) in methanol (30 mL) was added NaOH (13 mL of 2 M,26.0 mmol) and the reaction mixture was stirred for 4 hours at 50° C.The reaction was cooled to room temperature and the solvent was removedin vacuo. The residue was taken up in water and acidified with 2 M HCl.The mixture was extracted with ethyl acetate (×3) and the combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo to give the crude4-chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoicacid (1.21 g, 98%) as an orange oil. ESI-MS m/z calc. 463.03, found464.0 (M+1)+; Retention time (Method F): 0.78 minutes (1.5 minutes run).

Step 4: Methyl4-[[4-chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of4-chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoicacid (402 mg, 0.87 mmol) in DCM (13 mL) was added DMF (18 μL, 0.23 mmol)followed by dropwise addition of oxalyl chloride (235 μL, 2.68 mmol) andthe mixture was stirred for 1 hour. The reaction mixture wasconcentrated in vacuo to afford the acid chloride. A solution of thisacid chloride residue in DCM (13 mL) was then added dropwise to an icebath cooled solution of methyl 4-aminopyridine-2-carboxylate (162 mg,1.07 mmol) and N-ethyl-N-isopropyl-propan-2-amine (900 μL, 5.18 mmol).The resulting mixture was stirred at room temperature for 3 hours. Thesolvent was evaporated and the residue was purified by HPLC (37-100%acetonitrile/0.1% ammonium hydroxide) to provide methyl4-[[4-chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoyl]amino]pyridine-2-carboxylate(162 mg, 31%) as a white solid. ESI-MS m/z calc. 597.08, found 598.1(M+1)+; Retention time (Method F): 1.05 minutes (1.5 minutes run).

Step 5:4-[[4-Chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoyl]amino]pyridine-2-carboxamide(233)

A solution of methyl4-[[4-chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoyl]amino]pyridine-2-carboxylate(162.3 mg, 0.2715 mmol) and ammonia (8.8 mL of 7 M in methanol, 61.6mmol) was stirred at ambient temperature for 24 hours. The reactionmixture was concentrated in vacuo to provide a crude material which waspurified by HPLC (37-100% acetonitrile/0.1% ammonium hydroxide) toafford4-[[4-chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoyl]amino]pyridine-2-carboxamide(74 mg, 44%). ESI-MS m/z calc. 582.08, found 583.2 (M+1)+; Retentiontime (Method E): 3.39 minutes (5 minutes run). ¹H NMR (500 MHz, DMSO-d6)δ 11.30 (s, 1H), 8.54 (m, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.7Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (d, J=2.9 Hz, 1H), 7.36 (m,1H), 7.28 (t, J=52.7 Hz, 1H), 7.15 (dd, J=9.3, 2.1 Hz, 1H), 6.99 (s,1H), 3.91 (s, 3H) ppm.

Example 1794-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(223)

Step 1: Methyl4-[[2,6-difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To an ice cooled solution of 2,6-difluoro-4-(trifluoromethyl)benzoicacid (350 mg, 1.08 mmol) in DCM (5 mL) was added DMF (8 μL, 0.11 mmol)followed by dropwise addition of oxalyl chloride (28 μL, 3.25 mmol). Thereaction was stirred for 2 hours before concentrating in vacuo to affordthe acid chloride as a pale yellow oil. To a solution of this acidchloride in DCM (5 mL) in an ice bath was added methyl4-aminopyridine-2-carboxylate (HCl salt) (287 mg, 1.52 mmol) followed bytriethylamine (900 μL, 6.51 mmol). The resulting mixture was stirred andwarmed to room temperature over 2 hours. The reaction mixture wasquenched with water (10 mL) and extracted with DCM (2×10 mL). Thecombined organics were dried by phase separation cartridge andconcentrated in vacuo to afford methyl4-[[2,6-difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(205 mg, 53%) as a brown waxy solid. ESI-MS m/z calc. 360.05, found361.1 (M+1)+; 359.0 (M−1)−; Retention time (Method F): 0.85 minutes (1.5minutes run). ¹H NMR (500 MHz, CD₃OD) δ 8.50 (d, J=5.5 Hz, 1H), 8.30 (q,J=2.1 Hz, 1H), 7.89 (dd, J=5.5, 2.1 Hz, 1H), 7.29-7.22 (m, 2H), 4.33 (s,1H), 3.90 (s, 3H) ppm.

Step 2: Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

Methyl4-[[2,6-difluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(205 mg, 0.57 mmol), cesium carbonate (291 mg, 0.89 mmol) and3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (140 mg, 0.61mmol) were combined in DMF (3 mL) and stirred for 11 days at 30° C. Themixture was purified by HPLC (37-100% acetonitrile/0.1% ammoniumhydroxide) to afford methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(324 mg, 100%). ESI-MS m/z calc. 569.09, found 570.2 (M+1)+; 568.1(M−1)−; Retention time (Method F): 1.09 minutes (1.5 minutes). ¹H NMR(400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.63 (dd, J=5.4, 0.6 Hz, 1H), 8.35(dd, J=2.1, 0.6 Hz, 1H), 7.83-7.75 (m, 2H), 7.34 (ddt, J=8.1, 6.9, 1.3Hz, 1H), 7.27 (d, J=1.3 Hz, 1H), 7.11 (dd, J=9.3, 2.2 Hz, 1H), 3.89 (s,3H) ppm.

Step 3:4-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(223)

Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(100 mg, 0.176 mmol) was dissolved in ammonia (5 mL of 7 M in methanol,35 mmol) and stirred at 31° C. for 7 hours. The reaction mixture wasconcentrated in vacuo to afford4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(53 mg, 45%). ESI-MS m/z calc. 554.09, found 555.1 (M+1)+; 553.0 (M−1)−;Retention time (Method E): 3.42 minutes (5 minutes run). ¹H NMR (400MHz, DMSO-d6) δ 11.45 (s, 1H), 8.59-8.52 (m, 1H), 8.37-8.26 (m, 1H),8.10 (d, J=2.8 Hz, 1H), 7.83-7.74 (m, 2H), 7.66 (d, J=2.9 Hz, 1H), 7.35(ddt, J=8.1, 6.8, 1.2 Hz, 1H), 7.26 (d, J=1.3 Hz, 1H), 7.12 (dd, J=9.3,2.2 Hz, 1H) ppm.

Example 1804-[[2,4-Dichloro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(224)

Step 1: Methyl4-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxylate

To an ice-cooled solution of 2,4-dichloro-6-fluoro-benzoic acid (300 mg,1.01 mmol) in DCM (5 mL) was added DMF (8 μL, 0.10 mmol), followed bydropwise addition of oxalyl chloride (263 μL, 3.015 mmol) and reactionwas stirred for 2 hours. The reaction mixture was concentrated in vacuoto afford the acid chloride as a pale yellow oil. A solution of thisacid chloride in DCM (5 mL) was added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (HCl salt) (266 mg, 1.41 mmol) andtriethylamine (840 μL, 6.03 mmol) in an ice bath. The resulting mixturewas stirred and warmed to room temperature over 2 hours. Reactionmixture was quenched with water (10 mL) and extracted with DCM (2×10mL). The combined organics were dried by phase separation cartridge andconcentrated in vacuo to afford methyl4-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxylate (189 mg,55%) as a brown waxy solid. ESI-MS m/z calc. 342.00, found 343.0 (M+1)+;340.9 (M−1)−; Retention time (Method F): 0.82 minutes (1.5 minutes run).¹H NMR (400 MHz, CDCl₃) δ 10.23 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.30(d, J=2.1 Hz, 1H), 8.00 (dd, J=5.8, 2.1 Hz, 1H), 7.12 (t, J=1.6 Hz, 1H),6.99-6.91 (m, 1H), 3.88 (s, 3H) ppm.

Step 2: Methyl4-[[2,4-dichloro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

Methyl 4-[(2,4-dichloro-6-fluoro-benzoyl)amino]pyridine-2-carboxylate(189 mg, 0.55 mmol), cesium carbonate (282 mg, 0.87 mmol) and3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (134 mg, 0.58mmol) were combined in DMF (3 mL) and stirred for 11 days at 30° C. Anadditional equivalent of phenol was added and the temperature was raisedto 70° C. for 2 hours, then 110° C. overnight. The mixture was purifiedby HPLC (37-100% acetonitrile/0.1% ammonium hydroxide) to afford methyl4-[[2,4-dichloro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(8.5 mg, 3%). ESI-MS m/z calc. 551.03, found 552.1 (M+1)+; 550.0 (M−1)−;Retention time (Method F): 1.06 minutes (1.5 minutes run). ¹H NMR (400MHz, DMSO-d6) δ 11.41 (s, 1H), 8.62 (d, J=5.4 Hz, 1H), 8.37 (d, J=2.1Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.34(ddd, J=9.3, 8.1, 1.3 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.08 (dd, J=9.4,2.2 Hz, 1H), 3.88 (s, 3H) ppm.

Step 3:[[2,4-Dichloro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(224)

Methyl4-[[2,4-dichloro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(20 mg, 0.036 mmol) was dissolved in ammonia (1 mL of 7 M in methanol,7.0 mmol) and stirred at 31° C. for 7 hours. The reaction mixture wasconcentrated in vacuo and purified by HPLC (37-100% acetonitrile/0.1%ammonium hydroxide) to afford4-[[2,4-dichloro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(3.1 mg, 16%). ESI-MS m/z calc. 536.04, found 537.2 (M+1)+; 537.2(M−1)−; Retention time (Method E): 3.23 minutes (5 minute method). ¹HNMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.31 (d,J=2.1 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H),7.64 (dd, J=6.3, 2.4 Hz, 2H), 7.34 (ddd, J=9.3, 8.1, 1.3 Hz, 1H), 7.16(d, J=1.8 Hz, 1H), 7.09 (dd, J=9.3, 2.2 Hz, 1H) ppm.

Example 1814-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(225)

Step 1: 6-Bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid

To a suspension of 6-bromo-2-fluoro-3-(trifluoromethoxy)benzaldehyde(2.8 g, 9.76 mmol) in tert-butanol (15 mL), water (15 mL) andacetonitrile (15 mL) was added sodium dihydrogen phosphate (3.53 g, 29.4mmol) and 2-methyl-2-butene (5.6 mL, 52.9 mmol). Sodium chlorite (2.7 g,29.9 mmol) was added portionwise and the reaction was cooled in an icebath as an exotherm was observed during the addition. The reaction wasremoved from the ice bath and allowed to warm to room temperature. After20 minutes the reaction mixture was acidified with aqueous HCl (140 mLof 1 M, 140 mmol) and diluted with ethyl acetate. The two layers wereseparated and the aqueous layer washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo then purified by silica gelchromatography (0-15% methanol/dichloromethane with 0.2% AcOH) toprovide 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (2.10 g, 71%).ESI-MS m/z calc. 301.92, found 304.0 (M+1)+; Retention time (Method A):0.52 minutes (1 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 14.52 (br s,1H), 7.78-7.56 (m, 2H) ppm.

Step 2:2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicAcid

To a mixture of 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (400mg, 1.32 mmol),3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (274 mg, 1.20mmol) and cesium carbonate (460 mg, 1.41 mmol) in toluene (4.2 mL) wasadded copper (I) iodide (89 mg, 0.47 mmol) and the mixture was heated at100° C. with vigorous stirring for 18 hours. Reaction was cooled to roomtemperature then acidified with 2 M HCl, filtered and the aqueous layerwas extracted into ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to afford2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (580 mg, 97%). ESI-MS m/z calc. 451.04, found 452.0 (M+1)+;Retention time (Method F): 0.78 minutes (1.5 minutes run).

Step 3: Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (500 mg, 1.11 mmol) in DCM (12 mL) was added DMF (10 μL, 0.12 mmol)followed by dropwise addition of oxalyl chloride (290 μL, 3.324 mmol)and was stirred for 2 hours. The reaction mixture was concentrated invacuo to afford the acid chloride as a pale yellow waxy solid. Asolution of the acid chloride in DCM (12 mL) was added dropwise to asolution of methyl 4-aminopyridine-2-carboxylate (HCl salt) (294 mg,1.56 mmol) and triethylamine (925 μL, 6.64 mmol) in an ice bath. Theresulting mixture was stirred and warmed to room temperature overnight.The reaction mixture was concentrated in vacuo and purified by HPLC(37-100% acetonitrile/0.1% ammonium hydroxide) to afford methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxylate(160 mg, 25%) as a pale white solid. ESI-MS m/z calc. 585.09, found586.2 (M+1)+; 584.0 (M−1)−; Retention time (Method F): 1.05 minutes (1.5minute run). ¹H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.64 (dd, J=5.5,0.6 Hz, 1H), 8.36 (dd, J=2.2, 0.6 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H),7.76-7.66 (m, 1H), 7.41-7.31 (m, 1H), 7.14 (dd, J=9.3, 2.2 Hz, 1H), 6.93(dd, J=9.3, 1.7 Hz, 1H), 3.89 (s, 3H) ppm.

Step 4:4-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(225)

Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxylate(80 mg, 0.14 mmol) was dissolved in ammonia (3 mL of 7 M in methanol, 21mmol) and stirred at 40° C. for 5 hours. The reaction mixture wasconcentrated in vacuo to afford4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(64 mg, 81%). ESI-MS m/z calc. 570.09, found 571.5 (M+1)+; 569.0 (M−1)−;Retention time (Method E): 3.37 minutes (5 minutes run). ¹H NMR (400MHz, CDCl₃) δ 10.04 (s, 1H), 8.57-8.45 (m, 2H), 8.22 (d, J=2.2 Hz, 1H),7.87 (d, J=4.5 Hz, 1H), 7.36 (tq, J=8.1, 1.2 Hz, 1H), 7.09-6.92 (m, 2H),6.62 (dd, J=9.2, 1.7 Hz, 1H), 5.19 (d, J=4.6 Hz, 1H) ppm.

Example 1824-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(231)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide

To an ice-cooled solution of2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (prepared as described in Example 181, step 2, 580 mg, 1.23 mmol)in DCM (14 mL) was added DMF (10 μL, 0.14 mmol) followed by dropwiseaddition of oxalyl chloride (340 μL, 3.85 mmol). The reaction wasstirred for 2 hours then concentrated in vacuo to afford the acidchloride as a pale yellow waxy solid. A solution of this acid chloridein DCM (14 mL) was added dropwise to a solution of2-bromo-5-methyl-pyridin-4-amine (HCl salt) (404 mg, 1.81 mmol) andtriethylamine (1.07 mL, 7.67 mmol) in an ice bath. The resulting mixturewas stirred and warmed to room temperature and stirred for 18 hours. Thereaction mixture was concentrated in vacuo and purified by HPLC (37-100%acetonitrile/0.1% ammonium hydroxide) to affordN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide(185 mg, 23%) as a pale white solid. ESI-MS m/z calc. 619.01, found622.1 (M+1)+; 620.1 (M−1)−; Retention time (Method F): 1.15 minutes (1.5minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.25 (d, J=0.8Hz, 1H), 8.05 (s, 1H), 7.75-7.65 (m, 1H), 7.38 (ddt, J=9.4, 8.1, 1.2 Hz,1H), 7.13 (dd, J=9.3, 2.2 Hz, 1H), 6.91 (dd, J=9.3, 1.7 Hz, 1H), 2.19(d, J=0.7 Hz, 3H) ppm.

Step 2: Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide(180 mg, 0.29 mmol) was dissolved in methanol (9 mL), and triethylamine(88 μL, 0.63 mmol) and Pd(dppf)Cl₂.DCM (56 mg, 0.07 mmol) were added.Carbon monoxide was bubbled through the reaction mixture for 5 minutesat ambient temperature. The reaction mixture was sealed and heated at75° C. for 18 hours, then cooled to room temperature. The mixture wasconcentrated in vacuo and purified by HPLC (37-100% acetonitrile/0.1%ammonium hydroxide) to afford methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(84 mg, 48%) as a white solid. ESI-MS m/z calc. 599.10, found 600.2(M+1)+; 598.1 (M−1)−; Retention time (Method F): 1.05 minutes (1.5minutes run).

Step 3:4-[[2-Fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(231)

Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(84 mg, 0.14 mmol) was dissolved in ammonia (3 mL of 7 M in methanol, 21mmol) and stirred at 40° C. for 18 hours. The reaction mixture wasconcentrated in vacuo to afford4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(55 mg, 65%). ESI-MS m/z calc. 584.10, found 585.2 (M+1)+; 583.0 (M−1)−;Retention time (Method E): 3.39 minutes (5 minutes run). ¹H NMR (400MHz, CDCl₃) δ 8.84 (s, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 7.77 (d, J=4.4Hz, 1H), 7.35-7.22 (m, 1H), 7.15-6.95 (m, 2H), 6.64-6.51 (m, 1H), 5.89(d, J=4.5 Hz, 1H), 2.32 (s, 3H) ppm.

Example 1834-[[6-[3-Fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-(methylamino)-3-(trifluoromethoxy)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(230)

Methyl4-[[2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxylate(prepared as described in Example 181, step 3, 20 mg, 0.03 mmol) wasdissolved in methanamine (35 μL of 2 M, 0.07 mmol) and THF (0.5 mL) andstirred at 50° C. for 18 hours then 40° C. for 4 days. The reactionmixture was concentrated in vacuo to afford4-[[6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-(methylamino)-3-(trifluoromethoxy)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(6.3 mg, 31%). ESI-MS m/z calc. 595.14, found 596.0 (M+1)+; 594.4(M−1)−; Retention time (Method E): 3.47 minutes (5 minutes run). ¹H NMR(400 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.71 (q, J=4.8 Hz, 1H), 8.50 (d,J=5.5 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H),7.36-7.26 (m, 1H), 7.23 (dq, J=8.8, 1.6 Hz, 1H), 6.97 (dd, J=9.4, 2.2Hz, 1H), 6.13 (d, J=8.9 Hz, 1H), 6.00 (q, J=5.2 Hz, 1H), 2.81 (dd,J=6.5, 5.0 Hz, 6H) ppm.

Example 1844-[[2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(242)

Step 1:N-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide

To an ice-cooled solution of2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoic acid(prepared as described in Example 15, Step 1, 270 mg, 0.70 mmol) in DCM(4 mL) was added DMF (10 μL, 0.13 mmol) and dropwise oxalyl dichloride(295 μL, 3.38 mmol) and was stirred for 2 hours. The reaction mixturewas concentrated in vacuo to afford the acid chloride as a pale yellowoil. The residue was dissolved in DCM (4 mL) and added dropwise to asolution of 2-bromo-5-methyl-pyridin-4-amine (237 mg, 1.27 mmol) andtriethylamine (925 μL, 6.64 mmol) in DCM (4 mL) in an ice bath. Theresulting mixture was stirred and warmed to room temperature overnight.The reaction mixture was concentrated in vacuo and purified by silicagel chromatography (ethyl acetate/heptane) to affordN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(100 mg, 26%) as a clear waxy solid. ¹H NMR (400 MHz, CDCl3) δ 8.90 (s,1H), 8.31 (s, 1H), 8.07-8.02 (m, 1H), 7.46 (t, J=8.3 Hz, 1H), 7.24-7.16(m, 2H), 7.09-7.00 (m, 2H), 6.58 (d, J=8.8 Hz, 1H), 2.14 (d, J=0.7 Hz,3H) ppm.

Step 2: methyl4-[[2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(100 mg, 0.18 mmol) was dissolved in methanol (5 mL) and triethylamine(58 μL, 0.42 mmol) and Pd(dppf)Cl₂.DCM (42 mg, 0.05 mmol) were added. COgas was bubbled through the reaction mixture for 5 minutes whilst beingvigorously stirred at room temperature. The reaction mixture was sealedand heated to 75° C. overnight, then cooled to room temperature andconcentrated in vacuo to afford methyl4-[[2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(90 mg, 94%). ESI-MS m/z calc. 532.09, found 533.6 (M+1)+; 531.7 (M−1)−;Retention time (Method F): 0.97 minutes (1.5 minutes run).

Step 3:4-[[2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(242)

Methyl4-[[2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(90 mg, 0.17 mmol) was dissolved ammonia (5 mL of 7 M in methanol, 35mmol) and stirred at room temperature overnight. The reaction mixturewas concentrated in vacuo and purified by HPLC (37-100%acetonitrile/water/0.1% ammonium hydroxide) to afford4-[[2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(242, 1.8 mg, 2%). ESI-MS m/z calc. 517.09, found 518.6 (M+1)+; 516.7(M−1)−; Retention time (Method E): 3.24 minutes (5 minutes run). ¹H NMR(400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.47 (d, J=1.2 Hz, 2H), 8.05 (s,1H), 7.89 (t, J=8.6 Hz, 1H), 7.60 (s, 1H), 7.53-7.48 (m, 2H), 7.41-7.36(m, 2H), 6.91 (d, J=8.8 Hz, 1H), 2.27 (d, J=7.5 Hz, 3H) ppm.

Example 185N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[(6-methoxy-3-pyridyl)oxy]-3-(trifluoromethyl)benzamide(56)

A mixture of6-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-3-(trifluoromethyl)benzamide(75 mg, 0.18 mmol, prepared as described in Example 140), cesiumcarbonate (115 mg, 0.35 mmol) and 6-methoxypyridin-3-ol (22 mg, 0.18mmol) in toluene (1.9 mL) was bubbled with nitrogen. After 2-3 minutes,copper iodide (7 mg, 0.04 mmol) was added and the reaction mixture wasstirred at 100° C. for 20 minutes. The reaction was diluted with ethylacetate and water. The organic layer was concentrated in vacuo andpurified by HPLC (10-99% acetonitrile/5 mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[(6-methoxy-3-pyridyl)oxy]-3-(trifluoromethyl)benzamide(6 mg, 7%). ¹H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.15 (dd, J=3.0,0.6 Hz, 1H), 7.99 (dd, J=6.4, 2.8 Hz, 1H), 7.87-7.63 (m, 5H), 7.30 (dd,J=10.1, 8.9 Hz, 1H), 6.96 (dd, J=9.0, 0.6 Hz, 1H), 6.82 (d, J=8.9 Hz,1H), 3.87 (s, 3H) ppm.

Example 186N-(3-carbamoyl-4-fluoro-phenyl)-4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzamide(35)

Step 1: 4,5-dichloro-2-fluoro-N-methoxy-N-methyl-benzamide

A mixture of 4,5-dichloro-2-fluoro-benzoic acid (10 g, 47.9 mmol), HATU(20 g, 52.6 mmol) and N-methoxymethanamine (HCl salt) (4.67 g, 47.9mmol) in DMF (150 mL) was treated withN-ethyl-N-isopropyl-propan-2-amine (16.7 mL, 95.7 mmol) and was stirredat room temperature for 18 hours. The reaction mixture was concentratedin vacuo then diluted with diethyl ether and washed with 50% saturatedsodium bicarbonate solution (×2) and brine, dried over sodium sulfate,filtered and concentrated in vacuo. The product was purified by silicagel chromatography (0-30% ethyl acetate/hexanes) to provide4,5-dichloro-2-fluoro-N-methoxy-N-methyl-benzamide (11.5 g, 96%) as acolorless oil. ESI-MS m/z calc. 250.99, found 252.1 (M+1)+; Retentiontime (Method A): 0.54 minutes (1 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 7.87 (d, J=6.4 Hz, 1H), 7.84 (d, J=9.1 Hz, 1H), 3.52 (br s, 3H), 3.27(br s, 3H) ppm.

Step 2: 4,5-dichloro-2-fluoro-benzaldehyde

To a stirring solution of lithium aluminum hydride (25 mL of 2 M in THF,50.1 mmol) in THF (105 mL) at −78° C. was added a solution of4,5-dichloro-2-fluoro-N-methoxy-N-methyl-benzamide (10.5 g, 41.8 mmol)in anhydrous THF (53 mL) dropwise over 20 minutes whilst maintaininginternal reaction temperature less than −65° C. The reaction was stirredat −78° C. for 1 hour then was slowly poured into stirring aqueous 1 NHCl (210 mL of 1 M, 210 mmol) and ice. The mixture was extracted withdiethyl ether and the organic layer was washed with 1 N HCl and brine,then dried over sodium sulfate, filtered, and concentrated to provide4,5-dichloro-2-fluoro-benzaldehyde (7.98 g, 99%) as a white, creamysolid. ¹H NMR (400 MHz, DMSO-d6) δ 10.11 (d, J=0.5 Hz, 1H), 8.05 (d,J=6.7 Hz, 1H), 7.97 (d, J=10.1 Hz, 1H) ppm.

Step 3: 4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzaldehyde

A mixture of 4,5-dichloro-2-fluoro-benzaldehyde (502 mg, 2.60 mmol),2-methoxypyridin-3-ol (325 mg, 2.60 mmol) and cesium carbonate (1.02 g,3.12 mmol) in DMF (4 mL) was heated at 75° C. for 10 minutes. The cooledreaction mixture was diluted with ethyl acetate (50 mL) then partitionedwith water (50 mL). The aqueous portion was extracted with ethyl acetate(2×25 mL) and the combined organics were washed with saturated sodiumchloride solution (2×25 mL), dried over sodium sulfate concentrated invacuo. The product was purified by silica gel chromatography (0-100%ethyl acetate/hexanes) to provide4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzaldehyde (650 mg, 84%).ESI-MS m/z calc. 297.00, found 298.1 (M+1)+; Retention time (Method A):0.68 minutes (1 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H),8.12 (dd, J=5.0, 1.6 Hz, 1H), 7.97 (s, 1H), 7.70 (dd, J=7.7, 1.6 Hz,1H), 7.14-7.08 (m, 2H), 3.87 (s, 3H) ppm

Step 4: 4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzoic Acid

To a suspension of 4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzaldehyde(775 mg, 2.60 mmol) in t-butanol (5 mL), water (5 mL), acetonitrile (5mL) was added sodium dihydrogen phosphate (940 mg, 7.84 mmol),2-methyl-2-butene (1.4 mL, 13 mmol) and sodium chlorite (710 mg, 7.85mmol) and the mixture was stirred at room temperature for 1 hour. Thereaction mixture was acidified with 1 N HCl and diluted with ethylacetate. The layers were separated and the aqueous was extracted withethyl acetate (3×25 mL). The combined organics were washed with brine,dried over sodium sulfate and concentrated in vacuo to a light yellowsolid. The solid was slurried in hexane and filtered to provide4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzoic acid (610 mg, 75%).ESI-MS m/z calc. 312.99, found 314.1 (M+1)+; Retention time (Method A):0.59 minutes (1 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 13.40 (br s,1H), 8.04-7.97 (m, 2H), 7.38 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (s, 1H), 7.01(dd, J=7.7, 4.9 Hz, 1H), 3.87 (s, 3H) ppm.

Step 5: 4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzoyl chloride

To a solution of 4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzoic acid(610 mg, 1.94 mmol) and DMF (3 μL, 0.04 mmol) in DCM (9 mL) at roomtemperature was added oxalyl dichloride (850 μL, 9.74 mmol) dropwise.The reaction mixture was stirred for 10 minutes at room temperature thenconcentrated in vacuo and azeotroped with DCM (3×25 mL) to provide4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzoyl chloride (640 mg, 99%).The product was used in the next step without further purification.

Step 6:N-(3-carbamoyl-4-fluoro-phenyl)-4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzamide(35)

To a solution of 5-amino-2-fluoro-benzamide (23 mg, 0.15 mmol) andN-ethyl-N-isopropyl-propan-2-amine (78 μL, 0.45 mmol) in DCM (500 μL) at0° C. was added a solution of4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzoyl chloride (50 mg, 0.15mmol) in DCM (500 μL) dropwise. The reaction mixture was warmed to roomtemperature and stirred for 10 minutes, resulting in a thick slurry. Theslurry was filtered and the solid washed with minimal acetonitrile. Theresulting solid was re-suspended in water to obtain a white solid whichwas filtered and air dried. The solid was rinsed with hexanes and driedunder vacuum to provideN-(3-carbamoyl-4-fluoro-phenyl)-4,5-dichloro-2-[(2-methoxy-3-pyridyl)oxy]benzamide(30 mg, 45%) as a white solid. ESI-MS m/z calc. 449.03, found 450.1(M+1)+; Retention time (Method B): 1.59 minutes (3 minutes run). ¹H NMR(400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.02 (dd, J=4.9, 1.6 Hz, 1H),7.97-7.92 (m, 2H), 7.75 (ddd, J=9.0, 4.4, 2.8 Hz, 1H), 7.72-7.62 (m,2H), 7.52 (dd, J=7.8, 1.6 Hz, 1H), 7.26 (dd, J=10.2, 8.9 Hz, 1H), 7.15(s, 1H), 7.04 (dd, J=7.7, 4.9 Hz, 1H), 3.83 (s, 3H) ppm.

Example 187N-(3-carbamoyl-4-fluoro-phenyl)-2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzamide(162)

Step 1:2-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-4-(trifluoromethyl)benzamide

A mixture of 2-bromo-4-(trifluoromethyl)benzoic acid (400 mg, 1.49mmol), 5-amino-2-fluoro-benzamide (261 mg, 1.69 mmol), triethylamine(1.3 mL, 9.33 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (3 mL of 50% w/v, 4.71 mmol) in isopropyl acetate (8 mL)was heated at 100° C. over the weekend. The mixture was concentrated invacuo and partitioned between DCM and a saturated aqueous solution ofsodium bicarbonate. The organic portion was dried over magnesium sulfateand concentrated in vacuo to provide2-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-4-(trifluoromethyl)benzamide(620 mg, 103%) as a colourless oil. ESI-MS m/z calc. 403.98, found 405.0(M+1)+; 403.0 (M−1)−; Retention time (Method F): 0.81 minutes (1.5minutes run)

Step 2:N-(3-carbamoyl-4-fluoro-phenyl)-2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzamide(162)

A mixture of2-bromo-N-(3-carbamoyl-4-fluorophenyl)-4-(trifluoromethyl)benzamide (71mg, 0.18 mmol), (4-fluoro-2-methoxy-phenyl)boronic acid (50 mg, 0.29mmol), Pd(PPh₃)₄ (29 mg, 0.03 mmol) and sodium carbonate (300 μL of 2 M,0.60 mmol) in dioxane (4 mL) was heated for 2 hours at 140° C. in themicrowave. The mixture was concentrated in vacuo and purified by HPLC(0-100% acetonitrile/0.05% TFA) to provideN-(3-carbamoyl-4-fluoro-phenyl)-2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzamide(28 mg, 33%) as a white solid. ESI-MS m/z calc. 450.10, found 451.2(M+1)+; 449.2 (M−1)−; Retention time (Method E): 3.05 minutes (5 minutesrun). ¹H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.94-7.80 (m, 3H), 7.66(tt, J=4.5, 2.7 Hz, 4H), 7.36 (dd, J=8.4, 6.8 Hz, 1H), 7.23 (dd, J=10.1,8.9 Hz, 1H), 6.92 (dd, J=11.3, 2.5 Hz, 1H), 6.85 (td, J=8.4, 2.5 Hz,1H), 3.59 (s, 3H) ppm.

Example 188N-(4-carbamoyl-3-fluoro-phenyl)-6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzamide(67)

To a mixture of6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (96 mg, 0.26 mmol, prepared as described in Example 128) and HATU(111 mg, 0.29 mmol) in DMF (1.5 mL) was addedN-ethyl-N-isopropyl-propan-2-amine (102 μL, 0.58 mmol) and was stirredfor 10 minutes. 4-Amino-2-fluoro-benzamide (45 mg, 0.29 mmol) was thenadded and the reaction was stirred at 45° C. for 16 hours. Product waspurified by silica gel chromatography (0-10% methanol/DCM) then purifiedagain by HPLC (10-99% acetonitrile/5 mM HCl) to provideN-(4-carbamoyl-3-fluoro-phenyl)-6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzamide(5 mg, 3%). ESI-MS m/z calc. 501.05, found 502.0 (M+1)+; Retention time(Method B): 3.05 minutes (3 minutes run).

Example 1896-tert-butyl-N-(3-carbamoyl-4-fluoro-phenyl)-4-(4-fluoro-2-methoxy-phenyl)pyridine-3-carboxamide(199)

Step 1: 6-tert-butyl-4-chloro-pyridine-3-carboxylic Acid

Lithium hydroxide (3 mL of 2 M, 6.0 mmol) was added to a solution ofethyl 6-tert-butyl-4-chloro-pyridine-3-carboxylate (706 mg, 2.9 mmol) ina mixture of THF (8 mL), methanol (2 mL) and water (2 mL). The solutionwas stirred at room temperature for 18 hours before removing the organicsolvents in vacuo. The aqueous residue was acidified with 2 M HCl andthe mixture was extracted with DCM (×2). Combined organics were driedover magnesium sulfate, filtered and concentrated in vacuo to afford6-tert-butyl-4-chloro-pyridine-3-carboxylic acid (625 mg, 100%) as awhite solid. ESI-MS m/z calc. 213.06, found 214.1 (M+1)+; 212.1 (M−1)−;Retention time (Method F): 0.47 minutes (1.5 minutes run).

Step 2:6-tert-butyl-N-(3-carbamoyl-4-fluoro-phenyl)-4-chloro-pyridine-3-carboxamide

6-tert-Butyl-4-chloro-pyridine-3-carboxylic acid (207 mg, 0.97 mmol),5-amino-2-fluoro-benzamide (180 mg, 1.17 mmol), triethylamine (900 μL,6.46 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (2 mL of 50% w/v, 3.14 mmol) in isopropyl acetate (5 mL)was stirred at room temperature for 4 hours. The mixture wasconcentrated in vacuo and residue was partitioned between DCM andsaturated aqueous sodium bicarbonate. Layers were separated and theorganics dried over magnesium sulfate, filtered and concentrated invacuo to afford6-tert-butyl-N-(3-carbamoyl-4-fluoro-phenyl)-4-chloro-pyridine-3-carboxamide(340 mg, 100%) as a colourless oil. ESI-MS m/z calc. 349.10, found 350.2(M+1)+; 348.2 (M−1)−; Retention time (Method F): 0.8 minutes (1.5minutes run).

Step 3:6-tert-butyl-N-(3-carbamoyl-4-fluoro-phenyl)-4-(4-fluoro-2-methoxy-phenyl)pyridine-3-carboxamide(199)

6-tert-Butyl-N-(3-carbamoyl-4-fluoro-phenyl)-4-chloro-pyridine-3-carboxamide(149 mg, 0.43 mmol), (4-fluoro-2-methoxy-phenyl)boronic acid (107 mg,0.63 mmol), Pd(PPh₃)₄ (28 mg, 0.02 mmol), sodium carbonate (650 μL of 2M, 1.30 mmol) in dioxane (4 mL) was heated for 1 hour at 140° C. in amicrowave. The mixture was concentrated in vacuo and the residue waspurified by HPLC (0-100% acetonitrile/water/0.05% TFA) followed bypurification by HPLC (37-100% acetonitrile/water/0.1% ammoniumhydroxide) to afford6-tert-butyl-N-(3-carbamoyl-4-fluoro-phenyl)-4-(4-fluoro-2-methoxy-phenyl)pyridine-3-carboxamide(24 mg, 13%). ESI-MS m/z calc. 439.17, found 440.3 (M+1)+; 438.3 (M−1)−;Retention time (Method E): 2.96 minutes (5 minutes run). ¹H NMR (500MHz, DMSO-d6) δ 10.43 (s, 1H), 8.66 (s, 1H), 7.90 (dd, J=6.5, 2.8 Hz,1H), 7.67 (ddd, J=9.0, 4.4, 2.8 Hz, 2H), 7.61 (s, 1H), 7.42-7.31 (m,2H), 7.21 (dd, J=10.2, 8.9 Hz, 1H), 6.91-6.81 (m, 2H), 3.55 (s, 3H),1.36 (s, 9H) ppm.

Example 190N-(3-carbamoyl-4-fluoro-phenyl)-5-(4-fluoro-2-methoxy-phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(200)

Step 1:5-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide

5-Bromo-2-(trifluoromethyl)pyridine-4-carboxylic acid (107 mg, 0.40mmol), 5-amino-2-fluoro-benzamide (71 mg, 0.46 mmol), triethylamine (350μL, 2.51 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (800 μL of 50% w/v, 1.26 mmol) in isopropyl acetate (2mL) was stirred at room temperature for 1 hour. The mixture wasconcentrated in vacuo and the residue was partitioned between DCM andsaturated aqueous sodium bicarbonate. Layers were separated and theorganic layer dried over magnesium sulfate, filtered and concentrated invacuo to afford5-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(161 mg, 100%) as a colourless oil. ESI-MS m/z calc. 404.97, found 408.1(M+1)+; Retention time (Method F): 0.74 minutes (1.5 minutes run).

Step 2:N-(3-carbamoyl-4-fluoro-phenyl)-5-(4-fluoro-2-methoxy-phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(200)

5-Bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(161 mg, 0.40 mmol), (4-fluoro-2-methoxy-phenyl)boronic acid (106 mg,0.62 mmol), Pd(PPh₃)₄ (28 mg, 0.02 mmol) and sodium carbonate (600 μL of2 M solution in water, 1.20 mmol) were combined in dioxane (4 mL) andmixture was heated for 2 hours at 140° C. in a microwave. The mixturewas concentrated in vacuo and the residue was purified by HPLC (0-100%acetonitrile/water/0.05% TFA) to affordN-(3-carbamoyl-4-fluoro-phenyl)-5-(4-fluoro-2-methoxy-phenyl)-2-(trifluoromethyl)pyridine-4-carboxamide(Trifluoroacetic Acid (0.16)) (41 mg, 22%) as a white solid. ESI-MS m/zcalc. 451.10, found 452.2 (M+1)+; 450.2 (M−1)−; Retention time (MethodE): 2.78 minutes (5 minutes run). ¹H NMR (500 MHz, DMSO-d6) δ 10.66 (s,1H), 8.80 (s, 1H), 8.14 (d, J=0.6 Hz, 1H), 7.90 (dd, J=6.5, 2.8 Hz, 1H),7.75-7.59 (m, 3H), 7.46 (dd, J=8.4, 6.7 Hz, 1H), 7.26 (dd, J=10.1, 8.9Hz, 1H), 6.99 (dd, J=11.3, 2.5 Hz, 1H), 6.92 (td, J=8.4, 2.4 Hz, 1H),3.61 (s, 3H) ppm.

Example 191N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[[6-(trifluoromethoxy)-3-pyridyl]oxy]-3-(trifluoromethyl)benzamide(69)

6-Bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-3-(trifluoromethyl)benzamide(150 mg, 0.35 mmol, prepared as described in Example 140), cesiumcarbonate (231 mg, 0.71 mmol) and 6-(trifluoromethoxy)pyridin-3-ol(74.69 mg, 0.35 mmol) were combined in degassed toluene (1.5 mL). Tothis mixture was then added copper iodide (14 mg, 0.07 mmol) and thereaction was stirred at 100° C. for 20 minutes in a microwave. Thereaction was diluted with ethyl acetate and water. The organic layer waswashed with brine and dried over sodium sulfate then concentrated invacuo. The residue was triturated with hexane and filtered to affordN-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[[6-(trifluoromethoxy)-3-pyridyl]oxy]-3-(trifluoromethyl)benzamide(44 mg, 23%). ESI-MS m/z calc. 521.06, found 522.1 (M+1)+; Retentiontime (Method B): 1.69 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 11.08 (s, 1H), 8.34 (d, J=3.0 Hz, 1H), 7.97-7.80 (m, 3H), 7.80-7.63(m, 3H), 7.44 (d, J=8.9 Hz, 1H), 7.30 (dd, J=10.1, 9.0 Hz, 1H), 7.04 (d,J=8.8 Hz, 1H) ppm.

Example 1924-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(57)

To 4-aminopyridine-2-carboxamide (98 mg, 0.71 mmol), DMAP (17 mg, 0.14mmol) and N-ethyl-N-isopropyl-propan-2-amine (276 mg, 373 μL, 2.14 mmol)in DCM (3 mL), cooled to 0° C. and was added dropwise a solution of2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (300 mg, 0.71 mmol) in DCM (3 mL). The reaction was stirred atroom temperature for 18 hours. Mixture was concentrated in vacuo andpurified by silica gel chromatography (0-40% ethyl acetate/hexanes) toafford4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(28 mg, 7%). ESI-MS m/z calc. 521.06, found 522.1 (M+1)+; Retention time(Method B): 1.81 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ11.46 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.12 (d,J=2.7 Hz, 1H), 7.94 (t, J=8.6 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H),7.73-7.62 (m, 2H), 7.51 (dd, J=11.1, 2.8 Hz, 1H), 7.17 (ddd, J=9.1, 2.9,1.6 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H) ppm.

Example 1934-[[4-Chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(234)

Step 1: Methyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-formyl-benzoate

LDA (4.8 mL of 2 M, 9.6 mmol) was added dropwise to a solution of methyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(prepared as described in Example 177, Step 2, 3.49 g, 8.41 mmol) in THF(40 mL) at −78° C. The reaction was stirred at this temperature for 30minutes then DMF (34 mL, 439 mmol) was added dropwise over 15 minutesand the mixture was stirred at −78° C. for 30 minutes. The reaction wasquenched by the addition of water and was extracted with ethyl acetate(×3). The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to afford methyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-formyl-benzoate(3.92 g, 105%), which was used in the next step without purification.ESI-MS m/z calc. 443.03, found 442.1 (M−1)−; Retention time (Method F):1.08 minutes (1.5 minutes run).

Step 2: Methyl4-chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate

Deoxofluor (11.2 g, 50.7 mmol) in DCM (20 mL) was added to a solution ofmethyl4-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-formyl-benzoate(3.73 g, 8.40 mmol) in DCM (25 mL) and the reaction mixture was stirredat room temperature overnight. The reaction was quenched by pouring ontosaturated aqueous sodium bicarbonate and was stirred for 30 minutes atroom temperature. The layers were separated and the aqueous wasextracted with DCM (2×). Combined organic extracts were washed withwater then brine and concentrated in vacuo to afford methyl4-chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(3.96 g, 101%) as an orange oil, which was used in the next step withoutpurification.

Step 3:4-Chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicAcid

To a solution of methyl4-chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(3.9 g, 8.37 mmol) in THF (90 mL) was added NaOH (40 mL of 2 M, 80 mmol)and the reaction mixture was stirred at 70° C. overnight. The reactionwas cooled to room temperature and concentrated in vacuo. The residuewas taken up in water and acidified with 2 M HCl. The mixture wasextracted with ethyl acetate (×3) and the combined organic extracts weredried over MgSO₄, filtered and concentrated in vacuo to afford4-chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (4.02 g, 106%) as an orange oil, which was used in the next stepwithout purification.

Step 4: Methyl4-[[4-chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of4-chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (500 mg, 1.11 mmol) in DCM (17 mL) was added DMF (24 μL, 0.31 mmol)and dropwise oxalyl dichloride (303 μL, 3.47 mmol) and was stirred for 1hour. The reaction mixture was concentrated in vacuo to afford the acidchloride. A solution of the acid chloride in DCM (17 mL) was then addeddropwise to an ice-cooled solution of methyl4-aminopyridine-2-carboxylate (208 mg, 1.37 mmol) andN-ethyl-N-isopropyl-propan-2-amine (1.3 mL, 7.52 mmol) and was stirredat room temperature for 72 hours. The mixture was concentrated in vacuoand the residue was separated between 2 N aqueous NaOH and ethylacetate. The organic layer was washed with 1 M citric acid, then brine,dried over MgSO₄, filtered and concentrated in vacuo. The product waspurified by HPLC (37-100% acetonitrile/water/0.1% ammonium hydroxide) toprovide methyl4-[[4-chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(40 mg, 6%) as a white solid. ESI-MS m/z calc. 585.06, found 586.7(M+1)+; Retention time (Method F): 0.98 minutes (1.5 minutes run)

Step 5:4-[[4-Chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(234)

A solution of methyl4-[[4-chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(40 mg, 0.07 mmol) and 7 M ammonia in methanol (2.5 mL of 7 M, 17.5mmol) was stirred at room temperature for 24 hours. The reaction mixturewas concentrated in vacuo and purified by HPLC (37-100%acetonitrile/water/0.1% ammonium hydroxide) to provide4-[[4-chloro-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(234, 9 mg, 23%). ESI-MS m/z calc. 570.06, found 571.7 (M+1)+; Retentiontime (Method E): 3.34 minutes (5 minutes run). ¹H NMR (500 MHz, DMSO-d6)δ 11.45 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.10(d, J=2.8 Hz, 1H), 7.80 (d, J=5.2 Hz, 1H), 7.66 (s, 1H), 7.38 (t, J=53Hz, 1H), 7.37 (m, 1H), 7.20 (dd, J=9.4, 2.0 Hz, 1H), 7.13 (m, 1H) ppm.

Example 1944-[[3-(Difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (235)

Step 1:3-(Difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoic Acid

A suspension of 6-bromo-3-(difluoromethyl)-2-fluoro-benzoic acid(prepared as described in Example 75, Step 2, 1 g, 3.7 mmol),3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (prepared asdescribed in Example 169, Step 2, 941 mg, 4.11 mmol) and cesiumcarbonate (2.7 g, 8.29 mmol) in toluene (20 mL) was heated to 100° C.and then copper (I) iodide (145 mg, 0.76 mmol) was added. The mixturewas heated at 100° C. for 3 hours. The cooled reaction mixture wasconcentrated in vacuo then diluted with ethyl acetate and water thenacidified to pH 2 with 2 M HCl. The mixture was extracted with ethylacetate (2×100 mL). The combined organics were washed with water (2×100mL), brine (100 mL), dried over MgSO₄, filtered and concentrated invacuo to provide3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoic acid (1.48 g, 95%) as a brown gummy solid, which was used in thenext step without purification. ESI-MS m/z calc. 417.05, found 416.7(M−1)−; Retention time (Method F): 0.61 minutes (5 minutes run).Retention time: 0.61 minutes (1.5 minutes run). ¹H NMR (400 MHz,DMSO-d6) δ 13.90 (s, 1H), 7.71-7.62 (m, 1H), 7.41-7.32 (m, 1H),7.32-7.14 (m, 1H), 7.15-7.06 (m, 1H), 6.89-6.82 (m, 1H) ppm.

Step 2: Methyl4-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (300 mg, 0.72 mmol) in DCM (5 mL) was added DMF (9.3 μL, 0.12 mmol)and dropwise oxalyl dichloride (295 μL, 3.38 mmol) and was stirred for 2hours. The reaction mixture was concentrated in vacuo to afford the acidchloride as a pale yellow oil. The residue was dissolved in DCM (5 mL)and added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate(HCl salt) (290 mg, 1.54 mmol) and TEA (950 μL, 6.82 mmol) in DCM (5 mL)in an ice bath. The resulting mixture was stirred and warmed to roomtemperature overnight. The reaction mixture was concentrated in vacuo toafford methyl4-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(380 mg, 96%) as a brown oil, which was used in the next step withoutpurification. ESI-MS m/z calc. 551.10, found 552.3 (M+1)+; Retentiontime (Method F): 0.93 minutes (1.5 minutes run).

Step 3:4-[[3-(Difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(235)

Methyl4-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(380 mg, 0.69 mmol) was dissolved in 7 M ammonia in methanol (5 mL of 7M, 35 mmol) and stirred at room temperature overnight. The reactionmixture was concentrated in vacuo and the residue was purified by HPLC(37-100% acetonitrile/water/0.1% ammonium hydroxide) to provide4-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(235, 74 mg, 19%) as a white solid. ESI-MS m/z calc. 536.10, found 537.7(M+1)+; 535.8 (M−1)−; Retention time (Method E): 3.18 minutes (5 minutesrun). ¹H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.56 (d, J=5.5 Hz, 1H),8.33 (d, J=2.1 Hz, 1H), 8.10 (d, J=2.7 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz,1H), 7.73 (t, J=8.4 Hz, 1H), 7.66 (d, J=2.9 Hz, 1H), 7.41-7.35 (m, 1H),7.26 (s, 1H), 7.20-7.10 (m, 1H), 6.89 (d, J=8.7 Hz, 1H) ppm.

Example 1955-[[3-(Difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide (236)

Step 1: Methyl5-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (prepared as described in Example 194, Step 1, 300 mg, 0.72 mmol)in DCM (5 mL) was added DMF (9.3 μL, 0.12 mmol) and dropwise oxalyldichloride (295 μL, 3.38 mmol) and was stirred for 2 hours. The reactionmixture was concentrated in vacuo to afford the acid chloride as a paleyellow oil. The residue was dissolved in DCM (5 mL) and added dropwiseto a solution of methyl 5-aminopyridine-2-carboxylate (HCl salt) (290mg, 1.54 mmol) and TEA (950 μL, 6.82 mmol) in DCM (5 mL) in an ice bath.The resulting mixture was stirred and warmed to room temperatureovernight. The reaction mixture was concentrated in vacuo thenpartitioned between ethyl acetate and water. The organic portion wasdried over MgSO₄, filtered and concentrated in vacuo to afford methyl5-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(500 mg, 63%) as a brown oil, which was used in the next step withoutpurification. ESI-MS m/z calc. 551.10, found 552.8 (M+1)+; Retentiontime (Method F): 0.95 minutes (1.5 minutes run).

Step 2:5-[[3-(Difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(236)

Methyl5-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(380 mg, 0.3446 mmol) was dissolved in 7 M ammonia in methanol (6 mL of7 M, 42 mmol) and stirred at room temperature overnight. The reactionmixture was concentrated in vacuo and the residue was purified by HPLC(37-100% acetonitrile/water/0.1% ammonium hydroxide) to provide5-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(236, 63 mg, 34%) as a white solid. ESI-MS m/z calc. 536.10, found 537.7(M+1)+; 535.7 (M−1)−; Retention time (Method E): 3.12 minutes (5 minutesrun). ¹H NMR (400 MHz, CDCl₃) δ 9.32 (s, 1H), 8.80 (d, J=2.4 Hz, 1H),8.32 (dd, J=8.6, 2.5 Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.73 (d, J=4.1 Hz,1H), 7.57 (t, J=8.1 Hz, 1H), 7.15-7.00 (m, 2H), 6.84 (t, J=54.8 Hz, 1H),6.66 (d, J=8.8 Hz, 1H), 5.87 (d, J=4.2 Hz, 1H) ppm.

Example 1964-[[3-(Difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide (237)

Step 1:N-(2-bromo-5-methyl-4-pyridyl)-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzamide

To an ice-cooled solution of3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (prepared as described in Example 194, Step 1, 300 mg, 0.72 mmol)in DCM (5 mL) was added DMF (9.3 μL, 0.12 mmol) and dropwise oxalyldichloride (295 μL, 3.382 mmol) and was stirred for 2 hours. Thereaction mixture was concentrated in vacuo to afford the acid chlorideas a pale yellow oil. The residue was dissolved in DCM (5 mL) and addeddropwise to a solution of 2-bromo-5-methyl-pyridin-4-amine (HCl salt)(290 mg, 1.30 mmol) and triethylamine (950 μL, 6.82 mmol) in DCM (5 mL)in an ice bath. The resulting mixture was stirred and warmed to roomtemperature overnight. The reaction mixture was concentrated in vacuothen purified by column chromatography (ethyl acetate/heptane) to affordN-(2-bromo-5-methyl-4-pyridyl)-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzamide(100 mg, 24%) as a brown gummy solid. ESI-MS m/z calc. 585.02, found588.7 (M+1)+; Retention time (Method F): 1.07 minutes (1.5 minutes run).¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.16 (s, 1H), 8.07-8.00 (m, 1H),7.54 (ddt, J=8.6, 7.6, 1.0 Hz, 1H), 7.04 (ddq, J=8.8, 7.5, 1.2 Hz, 1H),6.97-6.93 (m, 1H), 6.85-6.66 (m, 1H), 6.57 (dd, J=8.7, 1.2 Hz, 1H), 2.09(d, J=0.8 Hz, 3H) ppm.

Step 2: Methyl4-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzamide(100 mg, 0.17 mmol) was dissolved in methanol (5 mL) and triethylamine(55 μL, 0.39 mmol) and Pd(dppf)Cl₂.DCM (40 mg, 0.049 mmol) were added.CO was bubbled through the reaction mixture for 5 minutes whilst beingvigorously stirred at room temperature. The reaction mixture was sealedand heated to 75° C. overnight, then cooled to room temperature andconcentrated in vacuo to afford methyl4-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(90 mg, 93%), which was used in the next step without purification.ESI-MS m/z calc. 565.12, found 566.7 (M+1)+; 564.7 (M−1)−; Retentiontime (Method F): 0.95 minutes (1.5 minutes run).

Step 3:4-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(237)

Methyl4-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(90 mg, 0.16 mmol) was dissolved in 7 M ammonia in methanol (5 mL of 7M, 35 mmol) and stirred at room temperature for 90 minutes, then at 40°C. for 2 hours. The reaction mixture was concentrated in vacuo and theresidue was purified by HPLC (37-100% acetonitrile/water/0.1% ammoniumhydroxide) to provide4-[[3-(difluoromethyl)-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(237, 9 mg, 9%). ESI-MS m/z calc. 550.12, found 551.1 (M+1)+; 549.0(M−1)−; Retention time (Method E): 3.21 minutes (5 minutes run). ¹H NMR(500 MHz, DMSO-d₆) δ 10.61 (s, 1H), 8.46 (d, J=13.4 Hz, 2H), 8.05 (d,J=2.7 Hz, 1H), 7.72 (t, J=8.3 Hz, 1H), 7.60 (s, 1H), 7.43-7.36 (m, 1H),7.27 (s, 1H), 7.18 (dd, J=9.6, 2.2 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 2.30(s, 3H) ppm.

Example 1974-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(240)

Step 1: 6-Bromo-3-chloro-2-fluoro-benzoic Acid

To a solution of methyl 6-bromo-3-chloro-2-fluoro-benzoate (500 mg, 1.87mmol) in methanol (10 mL) was added lithium hydroxide (5 mL of 2 M, 10mmol) and the reaction mixture was stirred at 50° C. for 1 hour. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was taken up in water and acidified with 2 M HCl. Themixture was extracted with ethyl acetate (×3) and the combined organicextracts were dried over MgSO₄, filtered and concentrated in vacuo toprovide 6-bromo-3-chloro-2-fluoro-benzoic acid (470 mg, 99%) as a whitecrystalline solid. ¹H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 7.71-7.56(m, 2H) ppm.

Step 2:3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoic Acid

A suspension of 6-bromo-3-chloro-2-fluoro-benzoic acid (245 mg, 0.97mmol), 3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (235mg, 1.03 mmol) and cesium carbonate (670 mg, 2.06 mmol) in toluene (5mL) was heated to 100° C. then copper (I) iodide (36 mg, 0.19 mmol) wasadded and the mixture was stirred at 100° C. overnight. The reactionmixture was cooled to room temperature then acidified to pH 2 with 2 MHCl. The mixture was extracted with ethyl acetate (2×100 mL). Theorganics were combined and washed with water (2×100 mL), brine (100 mL),dried over MgSO₄, filtered and concentrated in vacuo to afford3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (335 mg, 86%) as a brown gummy solid. ¹H NMR (400 MHz, CDCl3) δ7.43 (dd, J=9.0, 8.0 Hz, 1H), 7.06 (ddq, J=9.0, 7.7, 1.2 Hz, 1H), 6.90(dd, J=9.2, 2.3 Hz, 1H), 6.57 (dd, J=9.0, 1.6 Hz, 1H) ppm.

Step 3:N-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzamide

To an ice-cooled solution of3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (335 mg, 0.83 mmol) in DCM (6 mL) was added DMF (11 μL, 0.14 mmol)and dropwise oxalyl dichloride (350 μL, 4.01 mmol) and was stirred for 2hours. The reaction mixture was concentrated in vacuo to afford the acidchloride as a pale yellow oil. The residue was dissolved in DCM (6 mL)and added dropwise to a solution of 2-bromo-5-methyl-pyridin-4-amine(HCl salt) (336 mg, 1.50 mmol) and TEA (1.1 mL, 7.9 mmol) in DCM (6 mL)in an ice bath. The resulting mixture was stirred and warmed to roomtemperature overnight. The reaction mixture was concentrated in vacuoand purified by silica gel chromatography (ethyl acetate/heptane) toaffordN-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzamide(100 mg, 21%) as a brown waxy solid. ESI-MS m/z calc. 568.99, found572.5 (M+1)+; 570.5 (M−1)−; Retention time (Method F): 1.05 minutes (1.5minutes run). ¹H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.08 (d, J=6.2 Hz,2H), 7.35 (dd, J=9.0, 7.9 Hz, 1H), 7.02 (ddd, J=9.0, 7.7, 1.2 Hz, 1H),6.92 (dd, J=9.2, 2.2 Hz, 1H), 6.48 (ddd, J=9.0, 3.4, 1.6 Hz, 1H), 2.09(d, J=0.7 Hz, 3H) ppm.

Step 4: methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzamide(100 mg, 0.17 mmol) was dissolved in methanol (5 mL) and triethylamine(40 mg, 0.39 mmol) and Pd(dppf)Cl₂.DCM (40 mg, 0.049 mmol) were added.CO was bubbled through the reaction mixture for 5 minutes whilst beingvigorously stirred at room temperature. The reaction mixture was sealedand heated to 75° C. overnight, then cooled to room temperature andconcentrated in vacuo to afford methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(95 mg, 99%). ESI-MS m/z calc. 549.08, found 550.7 (M+1)+; 548.7 (M−1)−;Retention time (Method F): 0.96 minutes (1.5 minutes run).

Step 5:4-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(240)

Methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(95 mg, 0.17 mmol) was dissolved in ammonia (5 mL of 7 M in methanol, 35mmol) and stirred at room temperature for 90 minutes, then at 40° C. for2 hours. The reaction mixture was concentrated in vacuo and the residuewas purified by HPLC (37-100% acetonitrile/water/0.1% ammoniumhydroxide) to afford4-[[3-chloro-2-fluoro-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(240, 5 mg, 5%). ESI-MS m/z calc. 534.08, found 534.9 (M+1)+; 533.2(M−1)−; Retention time (Method E): 3.21 minutes (5 minutes run). ¹H NMR(400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.45 (d, J=16.6 Hz, 2H), 8.05 (s,1H), 7.70 (t, J=8.7 Hz, 1H), 7.62-7.57 (m, 1H), 7.36 (t, J=8.6 Hz, 1H),7.09 (dd, J=9.3, 2.1 Hz, 1H), 6.89 (dd, J=9.0, 1.4 Hz, 1H), 2.28 (s, 3H)ppm.

Example 1984-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide (241)

Step 1:2-Fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoic Acid

A suspension of 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (400mg, 1.32 mmol), 3-fluoro-4-(trifluoromethoxy)phenol (287 mg, 1.46 mmol)and cesium carbonate (950 mg, 2.92 mmol) in toluene (8 mL) was heated to100° C. then copper (I) iodide (53 mg, 0.28 mmol) was added. The mixturewas stirred at 100° C. over the weekend. The reaction mixture was cooledto room temperature then acidified to pH 2 with 2 M HCl. The mixture wasextracted with ethyl acetate (2×100 mL). The organics were combined andwashed with water (2×100 mL), brine (100 mL), dried over MgSO₄, filteredand concentrated in vacuo to afford2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (500 mg, 91%) as a brown gummy solid. ESI-MS m/z calc. 418.01,found 419.0 (M+1)+; Retention time (Method F): 0.63 minutes (1.5 minutesrun).

Step 2: methyl4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (500 mg, 1.20 mmol) in DCM (5 mL) was added DMF (16 μL, 0.21 mmol)and dropwise oxalyl dichloride (500 μL, 5.73 mmol) and the mixture wasstirred for 2 hours. The reaction mixture was concentrated in vacuo toafford the acid chloride as a yellow oil. The residue was dissolved inDCM (5 mL) and added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (330 mg, 2.17 mmol) and triethylamine (1.6mL, 11.5 mmol) in DCM (5 mL) in an ice bath. The resulting mixture wasstirred and warmed to room temperature overnight. The reaction mixturewas concentrated in vacuo and purified by silica gel chromatography(ethyl acetate/heptane) to afford methyl4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxylate(55 mg, 8%) as a white solid. ESI-MS m/z calc. 552.06, found 553.6(M+1)+; 551.7 (M−1)−; Retention time (Method F): 0.98 minutes (1.5minutes run). ¹H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.56 (d, J=5.5 Hz,1H), 8.10 (d, J=2.2 Hz, 1H), 7.94 (dd, J=5.8, 2.1 Hz, 1H), 7.27 (dddt,J=28.5, 9.5, 8.5, 1.1 Hz, 2H), 6.93-6.74 (m, 2H), 6.71 (dd, J=9.2, 1.8Hz, 1H), 3.87 (s, 3H) ppm.

Step 3:4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(241)

Methyl4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxylate(40 mg, 0.07 mmol) was dissolved in ammonia (3 mL of 7 M in methanol, 21mmol) and stirred at room temperature overnight. The reaction mixturewas concentrated in vacuo and the residue was purified by HPLC (37-100%acetonitrile/water/0.1% ammonium hydroxide) to afford4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(241, 8.1 mg, 20%). ESI-MS m/z calc. 537.06, found 538.6 (M+1)+; 536.7(M−1)−; Retention time (Method E): 3.35 minutes (5 minutes run). ¹H NMR(400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.55 (dd, J=5.4, 0.6 Hz, 1H), 8.26(dd, J=2.2, 0.6 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 7.82-7.72 (m, 2H),7.69-7.57 (m, 2H), 7.41 (dd, J=11.2, 2.9 Hz, 1H), 7.09 (tt, J=9.0, 2.3Hz, 2H) ppm.

Example 199N-(3-carbamoyl-4-methyl-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide(238)

This compound was made in an analogous fashion to Example 71, exceptemploying 5-amino-2-methyl-benzamide in the amide formation step (Step2). The yield of the desired product after purification was 38 mg (60%).ESI-MS m/z calc. 529.11, found 530.2 (M+1)+; retention time (Method B):1.23 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H),8.89 (s, 1H), 7.73 (s, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.64 (dd, J=8.2, 2.4Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J=2.8 Hz, 1H),7.22 (d, J=8.3 Hz, 1H), 7.10 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.99 (s,1H), 3.79 (s, 3H), 2.31 (s, 3H) ppm.

Example 200N-(3-carbamoyl-4-methoxy-phenyl)-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide(239)

This compound was made in an analogous fashion to Example 71, exceptemploying 5-amino-2-methoxy-benzamide in the amide formation step (Step2). The yield of the desired product after purification was 34 mg (49%).ESI-MS m/z calc. 545.10, found 546.2 (M+1)+; retention time (Method B):1.24 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H),8.91 (s, 1H), 8.11 (d, J=2.8 Hz, 1H), 7.86 (dd, J=9.0, 2.8 Hz, 1H), 7.68(s, 1H), 7.59 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H),7.15 (d, J=9.0 Hz, 1H), 7.09 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 7.00 (s,1H), 3.89 (s, 3H), 3.79 (s, 3H) ppm.

Example 201N-(3-carbamoyl-4-fluoro-phenyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(45)

This compound was made in an analogous fashion to Example 12, exceptemploying 5-amino-2-fluoro-benzamide in the amide coupling step (Step4). The yield of the desired product after purification was 40 mg (26%).ESI-MS m/z calc. 551.07, found 552.1 (M+1)+; retention time (Method B):1.77 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H),8.16 (s, 1H), 7.94 (dd, J=6.3, 2.8 Hz, 1H), 7.79-7.69 (m, 3H), 7.40 (d,J=8.8 Hz, 1H), 7.31 (dd, J=9.9, 9.1 Hz, 1H), 7.25 (d, J=2.6 Hz, 1H),7.07-6.99 (m, 1H), 3.80 (s, 3H) ppm.

Example 2024-[[3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(244)

Step 1:N-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide

To an ice-cooled solution of3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoic acid (preparedas described in Example 82, Step 2, 300 mg, 0.86 mmol) in DCM (5 mL) wasadded DMF (12 μL, 0.15 mmol) and dropwise oxalyl dichloride (360 μL,4.13 mmol) and the mixture was stirred and warmed to room temperatureover 2 hours. The reaction mixture was concentrated in vacuo to affordthe acid chloride as a pale yellow oil. The residue was dissolved in DCM(5 mL) and added dropwise to a solution of2-bromo-5-methyl-pyridin-4-amine (HCl salt) (345 mg, 1.54 mmol) and TEA(1.1 mL, 7.9 mmol) in DCM (5 mL) in an ice bath. The resulting mixturewas stirred and warmed to room temperature overnight. The reactionmixture was concentrated in vacuo to afford a brown mobile oil, whichwas purified by silica gel chromatography (ethyl acetate/heptane) toprovide a brown gummy solid. The product was re-purified by silica gelchromatography (DCM/methanol) to provideN-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(60 mg, 14%). ESI-MS m/z calc. 517.96, found 521.5 (M+1)+; 519.5 (M−1)−;Retention time (Method F): 1.07 minutes (1.5 minutes run). ¹H NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 8.07-7.96 (m, 2H), 7.34 (dd, J=9.0, 8.1 Hz,1H), 7.22-7.11 (m, 2H), 7.05-6.95 (m, 2H), 6.60 (dd, J=9.0, 1.6 Hz, 1H),2.09 (d, J=0.8 Hz, 3H) ppm.

Step 2: Methyl4-[[3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzamide(80 mg, 0.15 mmol) was dissolved in methanol (4 mL) and triethylamine(49 μL, 0.35 mmol) and Pd(dppf)Cl₂.DCM (35 mg, 0.043 mmol) were added.CO gas was bubbled through the reaction mixture for 5 minutes whilstbeing vigorously stirred at room temperature. The reaction mixture wassealed and heated to 75° C. overnight, then cooled to room temperatureand concentrated in vacuo to afford methyl4-[[3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate (70 mg, 91%).ESI-MS m/z calc. 498.06, found 499.6 (M+1)+; 497.6 (M−1)−; Retentiontime (Method F): 0.94 minutes (1.5 minutes run).

Step 3:4-[[3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(244)

Methyl4-[[3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(70 mg, 0.14 mmol) was dissolved in ammonia (5 mL of 7 M in methanol, 35mmol) and was stirred at room temperature overnight. The reactionmixture was concentrated in vacuo and purified by HPLC (37-100%acetonitrile/0.1% ammonium hydroxide) to provide4-[[3-chloro-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(9.4 mg, 13%) as an off-white solid. ESI-MS m/z calc. 483.06, found484.5 (M+1)+; Retention time (Method E): 3.09 minutes (5 minutes run).¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.43 (d, J=14.9 Hz, 2H), 8.05(d, J=2.8 Hz, 1H), 7.73 (t, J=8.8 Hz, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.44(dq, J=7.7, 1.0 Hz, 2H), 7.31-7.22 (m, 2H), 6.97-6.89 (m, 1H), 2.23 (s,3H) ppm.

Example 2034-[[3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(245)

Step 1: 6-bromo-3-chloro-2-fluoro-benzoic Acid

To a solution of methyl 6-bromo-3-chloro-2-fluoro-benzoate (400 mg, 1.50mmol) in methanol (10 mL) was added lithium hydroxide (5 mL of 2 M, 10mmol) and the reaction mixture was stirred at 50° C. for 3 hours. Thereaction was cooled to ambient temperature and concentrated in vacuo.The residue was taken up in water and acidified with 2 M HCl. Themixture was extracted with ethyl acetate (×3) and the combined organicswere dried (MgSO₄), filtered and concentrated in vacuo to provide6-bromo-3-chloro-2-fluoro-benzoic acid (370 mg, 98%) as a whitecrystalline solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.38 (s, 1H), 7.66 (dd,J=8.7, 7.7 Hz, 1H), 7.60 (dd, J=8.7, 1.1 Hz, 1H) ppm.

Step 2:3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzoic Acid

A suspension of 6-bromo-3-chloro-2-fluoro-benzoic acid (370 mg, 1.46mmol), 3-fluoro-4-(trifluoromethoxy)phenol (337 mg, 1.72 mmol) andcesium carbonate (1.06 g, 3.25 mmol) in toluene (15 mL) was heated to100° C. Copper (I) iodide (58 mg, 0.30 mmol) was added and the mixturewas stirred at 100° C. overnight. The reaction mixture was cooled toroom temperature then concentrated in vacuo, taken up in ethyl acetateand water and acidified to pH 2 with 2 M HCl. The mixture was extractedwith ethyl acetate (2×100 mL). The organics were combined and washedwith water (2×100 mL), brine (100 mL), dried (MgSO₄), filtered andconcentrated in vacuo to afford3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy) phenoxy]benzoic acid(500 mg, 93%) as a brown gummy solid, which was used in the next stepwithout purification.

Step 3:N-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzamide

To an ice-cooled solution of3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzoic acid(340 mg, 0.92 mmol) in DCM (5 mL) was added DMF (13 μL, 0.17 mmol) anddropwise oxalyl dichloride (390 μL, 4.47 mmol) and the mixture wasstirred for 2 hours. The reaction mixture was concentrated in vacuo toafford the acid chloride as a pale yellow oil. The residue was dissolvedin DCM (5 mL) and added dropwise to a solution of2-bromo-5-methyl-pyridin-4-amine (HCl salt) (370 mg, 1.65 mmol) andtriethylamine (1.19 mL, 8.54 mmol) in DCM (5 mL) in an ice bath. Theresulting mixture was stirred and warmed to room temperature over theweekend. The reaction mixture was concentrated in vacuo to afford abrown, mobile oil, which was purified by silica gel chromatography(ethyl acetate/heptane) to provide a brown gummy solid. The product wasre-purified by silica gel chromatography (DCM/methanol) to provideN-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzamide(160 mg, 32%). ESI-MS m/z calc. 535.96, found 539.5 (M+1)+; 537.5(M−1)−; Retention time (Method F): 1.07 minutes (1.5 minutes run). ¹HNMR (400 MHz, CDCl₃) δ 8.81 (d, J=7.6 Hz, 1H), 8.36 (d, J=4.0 Hz, 1H),8.15-8.10 (m, 1H), 7.45-7.36 (m, 1H), 7.30 (td, J=8.6, 1.2 Hz, 1H), 6.91(dd, J=10.4, 2.9 Hz, 1H), 6.71 (dd, J=9.0, 1.6 Hz, 1H), 2.21 (d, J=0.7Hz, 3H) ppm.

Step 4: methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzamide(100 mg, 0.19 mmol) was dissolved in methanol (5 mL) and triethylamine(60 μL, 0.43 mmol) and Pd(dppf)Cl₂.DCM (43 mg, 0.053 mmol) were added.CO gas was bubbled through the reaction mixture for 5 minutes whilstbeing vigorously stirred at room temperature. The reaction mixture wassealed and heated to 75° C. overnight, then cooled to room temperatureand concentrated in vacuo. The product was purified by HPLC (37-100%acetonitrile/0.1% ammonium hydroxide) to provide methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(20 mg, 21%). ESI-MS m/z calc. 516.05, found 517.6 (M+1)+; 515.6 (M−1)−;Retention time (Method F): 0.95 minutes (1.5 minutes run). ¹H NMR (400MHz, CDCl₃) δ 8.91 (s, 1H), 8.54 (s, 1H), 7.93 (s, 1H), 7.52 (t, J=8.4Hz, 1H), 7.33 (t, J=8.3 Hz, 1H), 6.95 (d, J=10.3 Hz, 1H), 6.87 (d, J=8.9Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 4.00 (s, 3H), 2.34 (s, 3H) ppm.

Step 5: 4-[[3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide (245)

Methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(20 mg, 0.039 mmol) was dissolved in ammonia (3 mL of 7 M in methanol,21 mmol) and stirred at room temperature over the weekend. Additionalammonia (2 mL of 7 M in methanol, 14 mmol) was added and the mixtureheated to 40° C. overnight. The reaction mixture was concentrated invacuo and the residue was purified by HPLC (26-100% acetonitrile/0.1%ammonium hydroxide) to provide4-[[3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(10 mg, 50%) as an off-white solid. ESI-MS m/z calc. 501.05, found 502.6(M+1)+; 500.6 (M−1)−; Retention time (Method E): 3.81 minutes (5 minutesrun). ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.47-8.37 (m, 2H), 8.04(s, 1H), 7.77 (t, J=8.7 Hz, 1H), 7.68-7.59 (m, 1H), 7.59 (s, 1H), 7.36(dd, J=11.5, 3.0 Hz, 1H), 7.07 (ddd, J=9.6, 7.2, 1.8 Hz, 2H), 2.19 (d,J=12.2 Hz, 3H) ppm.

Example 2044-[[3-chloro-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(246)

Step 1:N-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide

To an ice-cooled solution of2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (prepared as described in Example 18, Step 1, 480 mg, 1.19 mmol) inDCM (7 mL) was added DMF (16 μL, 0.21 mmol) and dropwise oxalyldichloride (500 μL, 5.73 mmol) and was stirred for 2 hours. The reactionmixture was concentrated in vacuo to afford the acid chloride as a paleyellow oil. The residue was dissolved in DCM (7 mL) and added dropwiseto a solution of 2-bromo-5-methyl-pyridin-4-amine (400 mg, 2.14 mmol)and TEA (1.57 mL, 11.3 mmol) in DCM (7 mL) in an ice bath. The resultingmixture was stirred and warmed to room temperature overnight. Thereaction mixture was concentrated in vacuo to afford a brown mobile oil,which was purified by silica gel chromatography (ethyl acetate/heptane)to provideN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(170 mg, 25%) as a clear waxy solid. ESI-MS m/z calc. 569.98, found573.5 (M+1)+; 569.6 (M−1)−; Retention time (Method F): 1.1 minutes (1.5minutes run).

Step 2: methyl4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tube,N-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(100 mg, 0.18 mmol) was dissolved in methanol (5 mL) and triethylamine(55 μL, 0.39 mmol) and Pd(dppf)Cl₂.DCM (40 mg, 0.05 mmol) were added. COgas was bubbled through the reaction mixture for 5 minutes whilst beingvigorously stirred at ambient temperature. The reaction mixture wassealed and heated to 75° C. overnight, then cooled to room temperatureand concentrated in vacuo. The residue was re-submitted to the sameconditions, with more vigorous bubbling of CO gas, then heatedovernight. The mixture was concentrated in vacuo, then purified by HPLC(37-100% acetonitrile/0.1% ammonium hydroxide) to provide methyl4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(30 mg, 31%). ESI-MS m/z calc. 550.08, found 551.6 (M+1)+; 549.6 (M−1)−;Retention time (Method F): 0.97 minutes (1.5 minutes run). ¹H NMR (400MHz, CDCl₃) δ 8.97 (s, 1H), 8.61 (s, 1H), 7.90 (s, 1H), 7.72 (s, 1H),7.40 (s, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 6.85 (d, J=8.4 Hz, 1H), 4.03(s, 3H), 2.40 (s, 3H) ppm.

Step 3:4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide (246)

Methyl4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate (30 mg, 0.06 mmol) wasdissolved in ammonia (4 mL of 7 M in methanol, 28 mmol) and stirred atroom temperature over the weekend. Additional ammonia (2 mL of 7 M inmethanol, 14 mmol) was added and the mixture heated to 40° C. overnight.The reaction mixture was concentrated in vacuo and the residue waspurified by HPLC (37-100% acetonitrile/0.1% ammonium hydroxide) toprovide4-[[2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(2.6 mg, 8%) as an off-white solid. ESI-MS m/z calc. 535.08, found 536.1(M+1)+; Retention time (Method E): 3.4 minutes (5 minutes run). ¹H NMR(400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.45 (d, J=5.8 Hz, 2H), 8.05 (s,1H), 7.91 (t, J=8.5 Hz, 1H), 7.68 (q, J=8.3 Hz, 1H), 7.59 (s, 1H), 7.48(dd, J=19.1, 11.1 Hz, 1H), 7.19 (d, J=9.2 Hz, 1H), 7.08 (d, J=8.9 Hz,1H), 2.24 (d, J=6.7 Hz, 3H) ppm.

Example 205N-(3-carbamoylphenyl)-2-(4-chloro-2-methoxyphenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(247)

Step 1: 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic Acid

A pressure flask was charged with 4-bromo-2-fluoro-benzoic acid (3 g,13.70 mmol) and copper (approximately 8.706 g, 137.0 mmol) in DMSO(56.25 mL). 1,1,1,2,2-Pentafluoro-2-iodo-ethane (approximately 23.58 g,95.90 mmol) was bubbled through the stirred solution. The vessel wassealed and heated at 120° C. for 72 hours. The reaction mixture wasdiluted with water and filtered through a plug of silica and thenextracted with ethylacetate (4×). The organic phases were combined,washed with brine, dried over sodium sulfate and evaporated to dryness.Purification by column chromatography (40 g silica; 0-40% ethylacetatein hexane) gave 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid(1.81 g, 51%) as white solid. ESI-MS m/z calc. 258.01154, found 259.3(M+1)+; retention time (Method B): 1.45 minutes (3 minute run).

Step 2: 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl chloride

To 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (300 mg, 1.162mmol) in toluene (3 mL) was added pyridine (4.7 μL, 0.058 mmol). Thereaction was heated at 60° C. under a nitrogen atmosphere. Sulfonylchloride (127 μL, 1.743 mmol) was added and the reaction stirred at 60°C. for 2 hours. Further sulfonyl chloride (127 μL, 1.743 mmol) wasadded. The solvent was then evaporated under reduced pressure. Toluene(1 mL) was added and the mixture was concentrated again to afford2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl chloride (321 mg, 100%),which was used in the next step without further purification.

Step 3:N-(3-carbamoylphenyl)-2-fluoro-4-(1,1,2,2,2-pentafluoroethylbenzamide

To 3-aminobenzamide (198 mg, 1.451 mmol) in MTBE (2 mL) and DMF (1 mL)was added potassium carbonate (481 mg, 3.483 mmol) in water (1.822 mL).The reaction was stirred at room temperature and2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl chloride (321 mg, 1.161mmol) in MTBE (2 mL) was added dropwise. The reaction was stirred atroom temperature overnight and then diluted with ethyl acetate (250 mL).The organic layer was separated, washed with brine, and evaporated underreduced pressure to giveN-(3-carbamoylphenyl)-2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzamide(398 mg, 91%) as a yellow solid, which was used in the next step withoutfurther purification. ¹H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H),8.26-8.12 (m, 1H), 8.04-7.90 (m, 2H), 7.90-7.80 (m, 2H), 7.71 (d, J=7.9Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.44 (dd, J=18.4, 10.6 Hz, 2H) ppm.

Step 4:N-(3-carbamoylphenyl)-2-(4-chloro-2-methoxyphenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(247)

ToN-(3-carbamoylphenyl)-2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzamide(50 mg, 0.13 mmol) and 4-chloro-2-methoxy-phenol (63 mg, 0.40 mmol) inDMF (0.5 mL) was added cesium carbonate (130 mg, 0.040 mmol). Thereaction was heated at 70° C. for one hour. The crude material waspurified by HPLC (1-99% acetonitrile in water (HCl modifier)) to obtainN-(3-carbamoylphenyl)-2-(4-chloro-2-methoxyphenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(18.4 mg, 26%). ESI-MS m/z calc. 514.07, found 515.3 (M+1)+; retentiontime (Method B): 1.64 minutes (3 minute run).

The compounds set forth in Table 13 were prepared by methods analogousto the preparation of compound 247.

TABLE 13 Additional Compounds Prepared By Methods Analogous to Compound247 in Example 205 Cmpd No. Compound Name LC/MS 248N-(3-carbamoylphenyl)-2-(4-fluoro- ESI-MS m/z calc. 498.10 found 499.22-methoxyphenoxy)-4-(1,1,2,2,2- (M + 1)+; Retention time (Method B):1.55 pentafluoroethyl)benzamide minutes (3 minute run). 249N-(3-carbamoylphenyl)-2-(4- ESI-MS m/z calc. 468.09 found 469.3fluorophenoxy)-4-(1,1,2,2,2- (M + 1)+; Retention time (Method B): 1.52pentafluoroethyl)benzamide minutes (3 minute run). 250N-(3-carbamoylphenyl)-2-(3-fluoro- ESI-MS m/z calc. 498.10 found 499.34-methoxyphenoxy)-4-(1,1,2,2,2- (M + 1)+; Retention time (Method B):1.50 pentafluoroethyl)benzamide minutes (3 minute run). 251N-(3-carbamoylphenyl)-2-(2-chloro- ESI-MS m/z calc. 514.07 found 515.24-methoxyphenoxy)-4-(1,1,2,2,2- (M + 1)+; Retention time (Method B):1.87 pentafluoroethyl)benzamide minutes (3 minute run). 252N-(3-carbamoylphenyl)-2-(2,4- ESI-MS m/z calc. 510.12 found 511.3dimethoxyphenoxy)-4-(1,1,2,2,2- (M + 1)+; Retention time (Method B):1.83 pentafluoroethyl)benzamide minutes (3 minute run).

Example 206N-(3-carbamoyl-4-methoxyphenyl)-2-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)benzamide(253)

Step 1: 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde

To a solution of 2-chloro-4-fluoro-phenol (20.97 g, 143.1 mmol) and2-fluoro-6-(trifluoromethyl)benzaldehyde (25.0 g, 130.1 mmol) in DMF(125 mL) was added cesium carbonate (46.6 g, 143.1 mmol) and thereaction mixture was stirred at 100° C. for 1 hour. The reaction mixturewas poured in to water (500 ml) and extracted with ethyl actetate (3×150ml). Organics were combined, washed with water, brine (2×), dried oversodium sulfate and evaporated to give a red oil which solidified afterstanding over night. The material was then triturated with hot hexanesand cooled to room temperature. The slurry was filtered and washed withcold hexanes to give2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (32.7 g,79%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H),7.84-7.70 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 7.47 (dd, J=9.0, 5.3 Hz, 1H),7.42-7.32 (m, 1H), 7.12 (d, J=8.3 Hz, 1H) ppm.

Step 2: 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid

To a solution of2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (31 g,97.29 mmol) in tert-butanol (155.0 mL), water (100.8 mL), acetonitrile(155.0 mL) and 2-methyl-2-butene (51.45 mL, 486.4 mmol) was added sodiumdihydrogen phosphate (18.29 mL, 291.9 mmol) and cooled to 0° C. Sodiumchlorite (26.40 g, 291.9 mmol) was added in one portion which caused andexotherm and the reaction mixture to reflux. The cooling bath wasremoved after 15 minutes and the reaction stirred at room temperaturefor 1 hour. The pH of the reaction mixture was adjusted to 2-3 with 1NHCl and the layers separated. The aqueous layer was extracted withethylactetate (3×), all organic layers were combined, and in theseparation funnel, solid sodium sulfite (˜5 g) was added followed bybrine (50 ml) and 1N NaOH (10 ml) and shaken until the yellow colour wasgone. The layers were separated and the organic was washed with brine,dried over sodium sulfate, filtered through a short plug of silica andevaporated to dryness to give2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (40 g,98%) as an oil that was used with out further purification.

Step 3:N-(3-carbamoyl-4-methoxyphenyl)-2-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)benzamide(253)

To 5-amino-2-methoxy-benzamide (16.6 mg, 0.1 mmol),2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (41.8 mg,0.1 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (38.0 mg, 0.1 mmol) in N-methyl pyrrolidinone (1 mL)was added triethylamine (42 μl, 0.3 mmol). The reaction mixture wasstirred at room temperature for 18 hours. The compound was filtered andpurified by reverse phase preparative chromatography utilizing agradient of 10-99% acetonitrile in water containing HCl as a modifier togiveN-(3-carbamoyl-4-methoxyphenyl)-2-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)benzamide(19.1 mg, 40%). ESI-MS m/z calc. 482.07, found 483.3 (M+1)+; retentiontime (Method B): 1.79 minutes (3 minute run).

The compounds set forth in Table 14 were prepared by methods analogousto the preparation of compound 253.

TABLE 14 Additional Compounds Prepared By Methods Analogous to Compound253 in Example 206 Cmpd No. Compound Name LC/MS 254N-(3-carbamoyl-4-chlorophenyl)-2- ESI-MS m/z calc. 486.02 found 487.3(2-chloro-4-fluorophenoxy)-6- (M + 1)+; Retention time (Method B): 1.83(trifluoromethyl)benzamide minutes (3 minute run). 255N-(5-carbamoyl-2-methylphenyl)-2- ESI-MS m/z calc. 466.07 found 467.3(2-chloro-4-fluorophenoxy)-6- (M + 1)+; Retention time (Method B): 1.75(trifluoromethyl)benzamide minutes (3 minute run).

Example 2075-[[2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(256)

Step 1: 5-aminopyridine-2-carboxylate

To a solution of 5-aminopyridine-2-carboxylic acid (276.2 mg, 2 mmol) inethanol (3 mL) was added sulphuric acid (53.3 μL, 1.0 mmol) and thereaction mixture was refluxed for 72 hours. The reaction mixture wasevaporated, taken up in ethyl acetate, washed with 1N NaOH (3×), driedover sodium sulfate and evaporated to dryness to give ethyl5-aminopyridine-2-carboxylate (150 mg, 90%) as a tan solid. ESI-MS m/zcalc. 166.07 found 167.3 (M+1)+; Retention time (Method B): 0.28 minutes(3 minute run). Used in the following step with out furtherpurification.

Step 2:5-[[2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(256)

2-(2-Chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (33.5 mg,0.10 mmol), ethyl 5-aminopyridine-2-carboxylate (20 mg, 0.12 mmol),N-methylmorpholine (22 μL, 0.2000 mmol) and HATU (42 mg, 0.11 mmol) inN-methyl pyrrolidinone (0.5 mL) were stirred at 80° C. for 8 hours. Thereaction mixture was poured into water and extracted with ethyl acetate(3×). The organic layers were combined, dried over sodium sulfate andevaporated to dryness. The material was taken up in ammonia in dioxane(500 μL of 0.5 M, 0.2500 mmol) and heated in a sealed tube at 100° C.for 72 h. The material was cooled, diluted with methanol and purified byHPLC (1-99% acetonitrile in water (HCl modifier)) to give5-[[2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(2.8 mg, 6%). ESI-MS m/z calc. 453.05 found 454.3 (M+1)+; Retention time(Method B): 1.47 minutes (3 minute run).

Example 208N-(3-carbamoylphenyl)-2-(4-fluorophenoxy)-6-(trifluoromethyl)benzamide(257)

Step 1: 2-(4-fluorophenoxy)-6-(trifluoromethyl)benzaldehyde

To a solution of 2-fluoro-6-(trifluoromethyl)benzaldehyde (1.0 g, 5.21mmol) and 4-fluorophenol (583 mg, 5.21 mmol) in DMF (5 mL) was addedcesium carbonate (1.70 g, 5.21 mmol) and the mixture was heated at 100°C. for 1 hour. The reaction was cooled to room temperature. The reactionwas diluted with ethyl acetate (5 ml) and water (10 ml). The organiclayer was washed with water (2×10 mL), dried over magnesium sulfate,filtered and evaporated to yield yellow oil. The mixture was purified bycolumn chromatography using a gradient of ethyl acetate in hexanes(0-50%) to afford 2-(4-fluorophenoxy)-6-(trifluoromethyl)benzaldehyde(800 mg, 54%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 10.60 (s,1H), 7.60-7.50 (m, 2H), 7.17-7.01 (m, 5H) ppm. ESI-MS m/z calc. 284.046,found 284.9 (M+1)+; Retention time (Method B): 2.03 minutes (3 minuterun).

Step 2: 2-(4-fluorophenoxy)-6-(trifluoromethyl)benzoic Acid

To a solution of 2-(4-fluorophenoxy)-6-(trifluoromethyl)benzaldehyde(2.23 g, 7.846 mmol) in tert-butanol (22.3 mL), water (14 mL) andacetonitrile (14 mL) was added sodium dihydrogen phosphate (1.48 mL,23.54 mmol), 2-methylbut-2-ene (4.15 mL, 39.25 mmol) and sodium chlorite(2.13 g, 23.54 mmol). The reaction mixture was stirred at 25° C. for 2h. The reaction was acidified with 1N HCl and was diluted with ethylacetate. Sodium sulfide was added to remove the faint yellow colour. Thetwo layers were separated and the aqueous layer extracted with ethylacetate (3×). The organics were combined, dried over sodium sulfate,filtered and concentrated to give2-(4-fluorophenoxy)-6-(trifluoromethyl)benzoic acid. ESI-MS m/z calc.300.041, found 301.5 (M+1)+; Retention time (Method B): 1.71 minutes (3min run).

Step 3:N-(3-carbamoylphenyl)-2-(4-fluorophenoxy)-6-(trifluoromethyl)benzamide(257)

Triethylamine (63 μL, 0.45 mmol) was added to a mixture of2-(4-fluorophenoxy)-6-(trifluoromethyl)benzoic acid (45 mg, 0.15 mmol),3-aminobenzamide (20.4 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol) and DMF(0.68 mL) at room temperature. The mixture was heated at 50° C. for 16hours before it was cooled to room temperature, filtered and subjectedto preparatory-HPLC (10-99% acetonitrile/water with 0.01% HCl) to giveN-(3-carbamoylphenyl)-2-(4-fluorophenoxy)-6-(trifluoromethyl)benzamide(27 mg, 43%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.99 (s, 1H),7.97 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.42-7.33 (m, 3H), 7.27 (t, J=6.3Hz, 1H), 6.99-6.90 (m, 5H), 6.50 (s, 1H), 5.74 (s, 1H) ppm. ESI-MS m/zcalc. 418.09, found 419.3 (M+1)+; retention time (Method B): 1.53minutes (3 minute run).

Example 209N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)benzamide(258)

Step 1: 2-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)benzaldehyde

To a solution of 2-fluoro-6-(trifluoromethyl)benzaldehyde (460 mg, 2.394mmol) and 4-fluoro-2-methyl-phenol (302.0 mg, 2.394 mmol) in DMF (3.942mL) was added cesium carbonate (780.0 mg, 2.394 mmol) and the mixturewas heated at 100° C. for 1 hour. The reaction was cooled to roomtemperature. The reaction was diluted with ethyl acetate (5 ml) andwater (10 ml). The organic layer was washed with water (2×10 mL), driedover magnesium sulfate, filtered and evaporated to yield a light brownoil (740 mg). The mixture was purified by column chromatography using agradient of ethyl acetate in hexanes (0-50%) over a period of 40minutes. 2-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)benzaldehyde(550 mg, 77%) was isolated as a transparent oil. ¹H NMR (400 MHz, CDCl₃)δ 10.59 (s, 1H), 7.46-7.36 (m, 2H), 6.95 (d, J=8.5 Hz, 1H), 6.86 (dd,J=6.1, 1.4 Hz, 2H), 6.80 (d, J=7.8 Hz, 1H), 2.14 (s, 3H) ppm. ESI-MS m/zcalc. 298.0617, found 299.3 (M+1)+; Retention time (Method B): 2.12minutes (3 minute run).

Step 2: 2-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)benzoic Acid

To a solution of2-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)benzaldehyde (745 mg,2.498 mmol) in tert-butanol (7.450 mL), water (4.694 mL) andacetonitrile (4.694 mL) was added sodium dihydrogen phosphate (899 mg,469.5 μL, 7.494 mmol), 2-methyl-2-butene (876 mg, 1.321 mL, 12.49 mmol)and sodium chlorite (679 mg, 7.494 mmol). The reaction mixture wasstirred at 25° C. for 3 h. The mixture was acidified with 1N HCl and wasdiluted with ethyl acetate. Sodium sulfite was added to remove theslightly yellow color. The two layers were separated and the aqueouslayer extracted 3 additional times with ethyl acetate. The organics werecombined, washed with brine, dried over sodium sulfate, filtered andconcentrated to give2-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)benzoic acid (660 mg,84%). ESI-MS m/z calc. 314.0566, found 315.3 (M+1)+; Retention time(Method B): 1.8 minutes (3 min run).

Step 3:N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)benzamide(258)

Triethylamine (63 μL, 0.45 mmol) was added to a mixture of2-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)benzoic acid (47 mg,0.15 mmol), 3-aminobenzamide (20.4 mg, 0.15 mmol), HATU (57 mg, 0.15mmol) and DMF (0.68 mL) at room temperature. The mixture was heated at50° C. for 16 hours before it was cooled to room temperature, filteredand subjected to preparatory-HPLC (10-99% acetonitrile/water with 0.01%HCl) to giveN-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)benzamide(23 mg, 35%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H),8.05 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.42-7.30(m, 3H), 6.95-6.88 (m, 2H), 6.86-6.79 (m, 2H), 6.39 (s, 1H), 5.54 (s,1H), 2.12 (s, 3H) ppm. ESI-MS m/z calc. 432.11 found 433.3 (M+1)+;Retention time (Method B): 1.58 minutes (3 minute run).

Example 210N-(3-carbamoylphenyl)-2-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)benzamide(259)

Step 1: 2-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)benzaldehyde

To a solution of 2-fluoro-6-(trifluoromethyl)benzaldehyde (2.00 g, 10.41mmol) and 4-fluoro-2-methoxy-phenol (1.480 g, 1.187 mL, 10.41 mmol) inDMF (17.14 mL) was added cesium carbonate (3.392 g, 10.41 mmol). Themixture was heated at 100° C. for 3 h. The mixture was cooled to roomtemperature before it was diluted with ethyl acetate and water. Thelayers were separated and the aqueous layer was extracted with ethylacetate (2×). The combined organics were washed with brine, dried oversodium sulfate, filtered and concentrated. The residue was purified bycolumn chromatography using a gradient of ethyl acetate in hexanes(0-100%) to give2-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)benzaldehyde (2.96 g,89%) as a clear oil that solidified upon standing. ¹H NMR (400 MHz,DMSO-d6) δ 10.63 (d, J=1.5 Hz, 1H), 7.69 (t, J=8.2 Hz, 1H), 7.56 (d,J=7.8 Hz, 1H), 7.32 (dd, J=8.8, 5.9 Hz, 1H), 7.19 (dd, J=10.7, 2.9 Hz,1H), 7.01 (d, J=8.5 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 3.76 (s, 3H)ppm. ESI-MS m/z calc. 314.0566, found 315.3 (M+1)+; Retention time(Method B): 2.0 minutes (3 min run).

Step 2: 2-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)benzoic Acid

To a solution of2-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)benzaldehyde (2.95 g,9.200 mmol) in tert-butanol (28.9 mL), water (18.2 mL) and acetonitrile(18.2 mL) was added sodium dihydrogen phosphate (1.73 mL, 27.60 mmol),2-methylbut-2-ene (4.87 mL, 46.00 mmol) and sodium chlorite (2.50 g,27.60 mmol). The reaction mixture was stirred at 25° C. for 3 h. Thereaction mixture was acidified with 1N HCl and was diluted with ethylacetate. Sodium sulfite was added to remove the faint yellow color. Thetwo layers were separated and the aqueous layer was extracted with ethylacetate (3×). The organics were combined, washed with brine, dried oversodium sulfate, filtered and concentrated to give2-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)benzoic acid (3.0 g,99%). ESI-MS m/z calc. 330.0515, found 331.5 (M+1)+; Retention time(Method B): 1.72 minutes (3 min run).

Step 3:N-(3-carbamoylphenyl)-2-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)benzamide(259)

Triethylamine (63 μL, 0.45 mmol) was added to a mixture of2-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)benzoic acid (49 mg,0.15 mmol), 3-aminobenzamide (20.4 mg, 0.15 mmol), HATU (57 mg, 0.15mmol) and DMF (0.68 mL) at room temperature. The mixture was heated at50° C. for 16 hours before it was cooled to room temperature, filteredand subjected to preparatory-HPLC (10-99% acetonitrile/water with 0.01%HCl) to giveN-(3-carbamoylphenyl)-2-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)benzamide(22 mg, 33%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H),8.06 (s, 1H), 7.82 (dd, J=8.1, 1.2 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H),7.43-7.33 (m, 3H), 7.09 (dd, J=8.8, 5.7 Hz, 1H), 6.90-6.83 (m, 1H), 6.73(dd, J=10.0, 2.8 Hz, 1H), 6.70-6.62 (m, 1H), 6.45 (s, 1H), 5.84 (s, 1H),3.77 (s, 3H) ppm. ESI-MS m/z calc. 448.10 found 449.3 (M+1)+; Retentiontime (Method B): 1.54 minutes (3 minute run).

Example 211N-(3-carbamoylphenyl)-2-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)benzamide(260)

Step 1: 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde

To a solution of 2-fluoro-6-(trifluoromethyl)benzaldehyde (580 mg, 3.019mmol) and 2-chloro-4-fluoro-phenol (442 mg, 319 μL, 3.02 mmol) in DMF(4.970 mL) was added cesium carbonate (984 mg, 3.019 mmol) and themixture was heated at 100° C. for 2.5 hours. The mixture was cooled toroom temperature before it was diluted with ethyl acetate and water. Thelayers were separated and the aqueous layer was extracted with ethylacetate (3×). The combined organics were washed with brine, dried oversodium sulfate, filtered and concentrated. The residue was purified bycolumn chromatography (0-100% ethyl acetate/hexanes) to yield2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (623 mg,65%). ¹H NMR (400 MHz, DMSO-d6) δ 10.61 (d, J=1.6 Hz, 1H), 7.78-7.70 (m,2H), 7.66 (d, J=7.7 Hz, 1H), 7.47 (dd, J=9.1, 5.2 Hz, 1H), 7.40-7.33 (m,1H), 7.12 (d, J=8.4 Hz, 1H) ppm. ESI-MS m/z calc. 318.00708, found 319.3(M+1)+; Retention time (Method B): 2.07 minutes (3 min run).

Step 2: 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid

To a solution of2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (610 mg,1.914 mmol) in tert-butanol (6.10 mL), water (3.84 mL) and acetonitrile(3.84 mL) was added sodium dihydrogen phosphate (689 mg, 360 μL, 5.742mmol), 2-methylbut-2-ene (671 mg, 1.01 mL, 9.570 mmol) and sodiumchlorite (519 mg, 5.742 mmol). The reaction mixture was stirred at 25°C. for 1 hour. The reaction was acidified with 1N HCl and was dilutedwith ethyl acetate. Sodium sulfite was added to remove the faint yellowcolor. The two layers were separated and the aqueous layer was extractedwith ethyl acetate (3×). The organics were combined, washed with brine,dried over sodium sulfate, filtered and concentrated to give2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (483 mg,75%). ESI-MS m/z calc. 334.00198, found 335.1 (M+1)+; Retention time(Method B): 1.78 minutes (3 min run).

Step 3:N-(3-carbamoylphenyl)-2-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)benzamide(260)

Triethylamine (63 μL, 0.45 mmol) was added to a mixture of2-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)benzoic acid (50 mg,0.15 mmol), 3-aminobenzamide (20.4 mg, 0.15 mmol), HATU (57 mg, 0.15mmol) and DMF (0.68 mL) at room temperature. The mixture was heated at50° C. for 16 hours before it was cooled to room temperature, filteredand subjected to preparatory-HPLC (10-99% acetonitrile/water with 0.01%HCl) to giveN-(3-carbamoylphenyl)-2-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)benzamide(24 mg, 36%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H),8.06 (s, 1H), 7.88 (dd, J=8.1, 1.1 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.42(d, J=4.0 Hz, 2H), 7.41-7.32 (m, 1H), 7.17 (dd, J=7.9, 3.0 Hz, 1H), 7.12(dd, J=9.0, 5.1 Hz, 1H), 6.97 (ddd, J=9.0, 7.6, 3.0 Hz, 1H), 6.83 (p,J=3.9 Hz, 1H), 6.43 (s, 1H), 5.74 (s, 1H) ppm. ESI-MS m/z calc. 452.06,found 453.3 (M+1)+; Retention time (Method B): 1.56 minutes (3 minuterun).

Example 2125-(4-(tert-butyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamido)nicotinamide(261)

A solution of 4-tert-butyl-2-[[6-(trifluoromethyl)-3-pyridyl]oxy]benzoicacid (34 mg, 0.1 mmol), 4-aminopyridine-2-carboxamide (15 mg, 0.11 mmol)and HATU (46 mg, 0.12 mmol) in DMF (0.5 mL) with N-methylmorpholine (33μL, 0.3 mmol) was stirred at room temperature for 16 hours. Purificationby HPLC (1-99% acetonitrile in water (HCl modifier)) afforded4-(4-(tert-butyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamido)picolinamide(23.4 mg, 51%). ESI-MS m/z calc. 458.16, found 459.3 (M+1)+; retentiontime (Method B): 1.57 minutes (3 minute run).

The compounds set forth in Table 15 were prepared by methods analogousto the preparation of compound 261.

TABLE 15 Additional Compounds Prepared By Methods Analogous to Compound261 in Example 212 Cmpd No. Compound Name LC/MS 262N-(3-carbamoylphenyl)-2-(4-fluoro- ESI-MS m/z calc. 458.16 found 459.52-methylphenoxy)-6- (M + 1)+; Retention time (Method B): 1.75(trifluoromethyl)benzamide minutes (3 minute run). 263N-(3-carbamoylphenyl)-2-(4-fluoro- ESI-MS m/z calc. 458.16 found 459.32-methoxyphenoxy)-6- (M + 1)+; Retention time (Method B): 1.78(trifluoromethyl)benzamide minutes (3 minute run).

Example 2134-(4-(tert-butyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamido)picolinamide(266)

A solution of 4-tert-butyl-2-[[6-(trifluoromethyl)-3-pyridyl]oxy]benzoicacid (34 mg, 0.1 mmol), 4-aminopyridine-2-carboxamide (15 mg, 0.11 mmol)and HATU (46 mg, 0.12 mmol) in DMF (0.5 mL) with N-methylmorpholine (33μL, 0.3 mmol) was stirred at room temperature for 16 hours. After 16hours, 4-dimethylaminopyridine (12 mg, 0.1 mmol) was added and thereaction mixture stirred at 60° C. for 2 h. Purification by HPLC (1-99%acetonitrile in water (HCl modifier)) afforded4-(4-(tert-butyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamido)picolinamide(3.11 mg, 7%). ESI-MS m/z calc. 458.16, found 459.5 (M+1)+; retentiontime (Method B): 1.70 minutes (3 minute run).

Example 214N-(3-carbamoylphenyl)-4,5-dichloro-2-(4-fluoro-2-methyl-phenoxy)benzamide(267)

Step 1: 4,5-dichloro-2-fluoro-benzoyl chloride

To 4,5-dichloro-2-fluoro-benzoic acid (4 g, 19.14 mmol) in toluene(40.00 mL) was added SOCl₂ (approximately 6.83 g, 4.2 mL, 57.42 mmol)and pyridine (approximately 75.7 mg, 77.4 μL, 0.957 mmol) and thereaction was heated to 80° C. under an inert atmosphere. After 4 hoursthe mixture as concentrated in vacuo, toluene was added and the mixtureas concentrated in vacuo (twice) to give 4,5-dichloro-2-fluoro-benzoylchloride (2.5 g, 57%) as pale solid which was used in the next stepwithout further purification.

Step 2: N-(3-carbamoylphenyl)-4,5-dichloro-2-fluoro-benzamide

To 3-aminobenzamide (approximately 2.02 g, 14.84 mmol) in MTBE (27 mL)and DMF (16 mL) was added K₂CO₃ (approximately 4.92 g, 35.61 mmol) inwater (15.33 mL). The reaction was stirred at room temperature, and4,5-dichloro-2-fluoro-benzoyl chloride (2.7 g, 11.87 mmol) in MTBE (27mL) was added drop wise. The mixture was stirred at room temperatureovernight. Ethyl acetate (250 mL) was added, and the organic layer waswashed with brine, and concentrated in vacuo to affordN-(3-carbamoylphenyl)-4,5-dichloro-2-fluoro-benzamide (1.2 g, 31%) as ayellow solid, which was used without further purification. ¹H NMR (400MHz, DMSO-d6) δ 10.69 (s, 1H), 8.28-8.11 (m, 1H), 8.03-7.96 (m, 2H),7.88 (dd, J=26.2, 8.9 Hz, 2H), 7.63 (d, J=7.7 Hz, 1H), 7.51-7.32 (m,2H).

Step 3:N-(3-carbamoylphenyl)-4,5-dichloro-2-(4-fluoro-2-methyl-phenoxy)benzamide(267)

To a solution of N-(3-carbamoylphenyl)-4,5-dichloro-2-fluoro-benzamide(60 mg, 0.183 mmol) and 4-fluoro-2-methyl-phenol (approximately 25 mg,0.201 mmol) in DMF (0.3 mL) was added K₂CO₃ (approximately 76 mg, 0.550mmol). The mixture was stirred at 70° C. for 40 min, then at roomtemperature overnight. The mixture was purified by HPLC to provideN-(3-carbamoylphenyl)-4,5-dichloro-2-(4-fluoro-2-methyl-phenoxy)benzamide(2 mg, 2.5%). ESI-MS m/z calc. 432.04, found 433.16 (M+1)+; Retentiontime (Method B): 1.89 minutes (3 minutes run).

The compounds set forth in Table 16 were prepared by methods analogousto the preparation of compound 267.

TABLE 16 Additional Compounds Prepared By Methods Analogous to Example214 Cmpd No. Compound Name LC/MS 268 N-(3-carbamoylphenyl)-4,5- ESI-MSm/z calc. dichloro-2-(4- 418.03, found fluorophenoxy)benzamide 419.13(M + 1)+; Retention time (Method B): 1.77 minutes (3 minute run). 269N-(3-carbamoylphenyl)-4,5- ESI-MS m/z calc. dichloro-2-(2,4- 460.06,found dimethoxyphenoxy)benzamide 461.18 (M + 1)+; Retention time (MethodB): 1.87 minutes (3 minute run). 270 N-(3-carbamoylphenyl)-4,5- ESI-MSm/z calc. dichloro-2-(4-fluoro-2- 448.04, foundmethoxy-phenoxy)benzamide 449.15 (M + 1)+; Retention time (Method B):1.83 minutes (3 minute run). 271 N-(3-carbamoylphenyl)-4,5- ESI-MS m/zcalc. dichloro-2-(3-fluoro-4- 448.04, found methoxy-phenoxy)benzamide449.15 (M + 1)+; Retention time (Method B): 1.79 minutes (3 minute run).272 N-(3-carbamoylphenyl)-4,5- ESI-MS m/z calc. dichloro-2-[4- 484.02,found (trifluoromethoxy)phenoxy]benzamide 485.16 (M + 1)+; Retentiontime (Method B): 1.95 minutes (3 minute run). 273N-(3-carbamoylphenyl)-4,5- ESI-MS m/z calc. dichloro-2-(2-fluoro-4-448.04, found methoxy-phenoxy)benzamide 449.15 (M + 1)+; Retention time(Method B): 1.81 minutes (3 minute run).

Example 215N-(4-carbamoylphenyl)-4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzamide(274)

Step 1: 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzaldehyde

To a stirring solution of4,5-dichloro-2-fluoro-N-methoxy-N-methyl-benzamide (5.1 g, 20.23 mmol,prepared as described in Example 286) in THF (100 mL) at −78° C. wasadded a solution of lithium aluminum hydride in THF (approximately 12.14mL of 2 M, 24.28 mmol). After 3 hours at −78° C., 50 mL of water wasadded followed by 50 mL of 1 N HCl. The reaction was allowed to warm toroom temperature and stirred for 1 hour. The reaction was diluted withwater and extracted with diethyl ether. The ether layer was dried overNa₂SO₄, filtered, and concentrated to provide crude4,5-dichloro-2-fluoro-benzaldehyde. The aldehyde was taken directly tothe next step.

Crude 4,5-dichloro-2-fluoro-benzaldehyde, 4-fluoro-2-methoxy-phenol(approximately 2.875 g, 2.306 mL, 20.23 mmol) and K₂CO₃ (approximately5.592 g, 40.46 mmol) were combined in DMF (100 mL) and heated for 30 minat 70° C., then at 55° C. overnight. The reaction was cooled, dilutedwith water (500 mL) and extracted with diethyl ether. The ether layerwas dried over Na₂SO₄, filtered, and concentrated. Silica gelchromatography (120 g silica, 0-40% ethyl acetate/hexane) provided4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzaldehyde (3.30 g, 52%) asa crystalline white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H),7.93 (s, 1H), 7.35 (dd, J=8.8, 5.8 Hz, 1H), 7.19 (dd, J=10.7, 2.9 Hz,1H), 6.92-6.85 (m, 2H), 3.78 (s, 3H).

Step 2: 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoic Acid

To a solution of 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzaldehyde(3.3 g, 10.47 mmol) in tert-butyl alcohol (33 mL), water (19.8 mL) andacetonitrile (19.8 mL) was added sodium dihydrogen phosphate(approximately 1.256 g, 656 μL, 10.47 mmol), 2-methylbut-2-ene(approximately 3.671 g, 5.54 mL, 52.35 mmol) and sodium chlorite(approximately 2.841 g, 31.41 mmol). The reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was acidified with 1NHCl and diluted with ethyl acetate. Sodium sulfite was added to removethe faint yellow color. The two layers were separated and the aqueouslayer was extracted with ethyl acetate (3×25 mL). The combined organicswere washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The solid was triturated with hexane and filteredto provide 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoic acid (2.94g, 85%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 13.37 (br s, 1H),7.96 (s, 1H), 7.18-7.12 (m, 2H), 6.86-6.80 (m, 2H), 3.76 (s, 3H).

Step 3: 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoicacid-(4-carbamoylphenyl)-4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzamide(274)

4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoic acid (40 mg, 0.1208mmol), 4-aminobenzamide (approximately 16.45 mg, 0.1208 mmol), and HATU(approximately 45.93 mg, 0.1208 mmol) were dissolved in DMF (0.5 mL) andstirred at 45° C. for 16 hours. The crude material was purified by HPLC(10-99% CH3CN/5 mM HCl) to give4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoicacid-(4-carbamoylphenyl)-4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzamide%). ESI-MS m/z calc. 448.04, found 449.3 (M+1)+; Retention time (MethodB): 1.79 minutes (3 min run).

Example 216N-(3-carbamoylphenyl)-2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzamide(275)

Step 1: 2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzaldehyde

To a solution of 2-fluoro-6-methyl-benzaldehyde (1.07 g, 7.746 mmol) and2-chloro-4-fluoro-phenol (approximately 1.135 g, 817.7 μL, 7.746 mmol)in DMF (9.169 mL) was added cesium carbonate (approximately 2.524 g,7.746 mmol), and the mixture was heated at 100° C. for 1 hour. Themixture was cooled to room temperature before it was diluted with ethylacetate and water. The layers were separated and the aqueous layer wasextracted with ethyl acetate (3×). The combined organics were washedwith brine, dried over sodium sulfate, filtered and concentrated. Theresidue was purified by column chromatography using a gradient of ethylacetate in hexanes (0-100%) to yield2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzaldehyde (1.05 g, 51%).ESI-MS m/z calc. 264.03534, found 265.1 (M+1)+; Retention time (MethodB): 2.02 minutes (3 min run).

Step 2: 2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzoic Acid

To a solution of 2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzaldehyde(1.05 g, 3.967 mmol) in tBuOH (10.50 mL), water (6.615 mL) andacetonitrile (6.615 mL) was added sodium dihydrogen phosphate(approximately 1.428 g, 745.7 μL, 11.90 mmol), 2-methylbut-2-ene(approximately 1.391 g, 2.098 mL, 19.83 mmol) and sodium chlorite(approximately 1.076 g, 11.90 mmol). The reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was acidified with 1NHCl and was diluted with ethyl acetate. Sodium sulfite was added toremove the faint yellow color. The two layers were separated and theaqueous layer was extracted with ethyl acetate (3×). The organics werecombined, washed with brine, dried over sodium sulfate, filtered andconcentrated to give 2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzoic acid(1.06 g, 95%). ESI-MS m/z calc. 280.03024, found 281.5 (M+1)+; Retentiontime (Method B): 1.7 minutes (3 min run).

Step 3:N-(3-carbamoylphenyl)-2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzamide(275)

Triethyl amine (approximately 109.9 mg, 151.4 μL, 1.086 mmol) was addedto a mixture of 2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzoic acid (61mg, 0.217 mmol), 3-aminobenzamide (approximately 29.59 mg, 0.217 mmol),HATU (approximately 82.62 mg, 0.217 mmol) and DMF (1.220 mL) at roomtemperature. The mixture was heated at 50° C. for 5 hours before it wascooled to room temperature, filtered and subjected to preparatory-HPLC(10-99% ACN/water with 0.01% HCl) to affordN-(3-carbamoylphenyl)-2-(2-chloro-4-fluoro-phenoxy)-6-methyl-benzamide(5.3 mg, 6%). ESI-MS m/z calc. 398.08334, found 399.5 (M+1)+; Retentiontime (Method B): 1.61 minutes (3 min run). ¹H NMR (400 MHz, DMSO) δ10.62 (s, 1H), 8.20 (t, J=1.7 Hz, 1H), 7.95 (s, 1H), 7.78 (dd, J=8.0,1.4 Hz, 1H), 7.61-7.54 (m, 2H), 7.43-7.34 (m, 2H), 7.33-7.23 (m, 3H),7.10 (d, J=7.6 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 2.35 (s, 3H).

Example 217N-(3-carbamoylphenyl)-2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamide(276)

Step 1: N-(3-carbamoylphenyl)-2-fluoro-5-(trifluoromethyl)benzamide

To a stirring solution of 3-aminobenzamide (6.0 g, 44.1 mmol), DCM (100mL), DMF (30 mL) and pyridine (35 g, 36 mL, 441 mmol), at 00 C(ice-bath), was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (10g, 44.1 mmol) dropwise over a period of 10 minutes. The reaction mixturewas stirred at 00 C for 1 hour, the ice bath was removed, and thereaction mixture was allowed to stir at room temperature for 4 hours.The reaction mixture was filtered and the solid was washed with aminimum amount of ethyl acetate and water. The obtained solid was driedin a vacuum oven to yieldN-(3-carbamoylphenyl)-2-fluoro-5-(trifluoromethyl)benzamide (12.7 g,88%) as an off-white solid. ESI-MS m/z calc. 326.08, found 327.3 (M+1)⁺;retention time (Method B): 1.39 (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 10.73 (s, 1H), 8.20-8.14 (m, 1H), 8.08 (dd, J=6.1, 2.4 Hz,1H), 8.06-7.93 (m, 2H), 7.87 (dd, J=7.9, 2.1 Hz, 1H), 7.69-7.59 (m, 2H),7.45 (t, J=7.9 Hz, 1H), 7.40 (s, 1H) ppm.

Step 2:N-(3-carbamoylphenyl)-2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamide(276)

A reaction vial was loaded withN-(3-carbamoylphenyl)-2-fluoro-5-(trifluoromethyl)benzamide (51 mg, 0.15mmol), 4-fluoro-phenol (17 mg, 0.15 mmol), cesium carbonate (147 mg,0.45 mmol), and NMP (1 mL), and the reaction mixture was heated at 1000C for 30 minutes. The reaction mixture was filtered and purified byreverse phase HPLC (gradient of 10-99% acetonitrile in water containingHCl as a modifier) to obtainN-(3-carbamoylphenyl)-2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamide(36 mg, 58%) as a white solid. ESI-MS m/z calc. 418.09, found 419.2(M+1)+; retention time (Method B): 1.73 (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 10.62 (s, 1H), 8.19-8.13 (m, 1H), 8.00 (d, J=2.2 Hz, 1H),7.96 (s, 1H), 7.89-7.78 (m, 2H), 7.63-7.55 (m, 1H), 7.47-7.35 (m, 2H),7.35-7.23 (m, 4H), 6.99 (d, J=8.7 Hz, 1H).

The compounds set forth in Table 17 were prepared by methods analogousto the preparation of compound 276.

TABLE 17 Additional Compounds Prepared By Methods Analogous to Example217 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 277N-(3-carbamoylphenyl)-2- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δphenoxy-5- 400.10, found 401.4 10.62 (s, 1H), 8.20-8.10 (m, 1H),(trifluoromethyl)benzamide (M + 1)+; Retention 8.00 (d, J = 2.3 Hz, 1H),7.96 (s, time (Method B): 1H), 7.91-7.76 (m, 2H), 1.72 minutes (37.64-7.54 (m, 1H), 7.52-7.33 (m, 4H), minute run). 7.30-7.16 (m, 3H),7.02 (d, J = 8.8 Hz, 1H). 278 N-(3-carbamoylphenyl)-2-(3- ESI-MS m/zcalc. ¹H NMR (400 MHz, DMSO-d6) δ fluoro-2-methoxyphenoxy)-5- 448.10,found 10.64 (s, 1H), 8.24-8.14 (m, 1H), (trifluoromethyl)benzamide 449.3(M + 1)+; 8.01 (d, J = 2.3 Hz, 1H), 7.96 (s, Retention time 1H),7.89-7.78 (m, 2H), (Method B): 1.75 7.64-7.55 (m, 1H), 7.48-7.31 (m,2H), minutes (3 minute 7.30-7.13 (m, 2H), run). 7.13-7.05 (m, 1H), 6.97(d, J = 8.7 Hz, 1H), 3.78 (d, J = 1.0 Hz, 3H). 279N-(3-carbamoylphenyl)-2-(2- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δchloro-4-methoxyphenoxy)- 464.08, found 465.3 10.60 (s, 1H), 8.24-8.15(m, 1H), 5-(trifluoromethyl)benzamide (M + 1)+; Retention 8.02-7.94 (m,2H), time (Method B): 7.90-7.84 (m, 1H), 7.79 (dd, J = 8.9, 2.4 Hz, 1.82minutes (3 1H), 7.65-7.54 (m, 1H), minute run). 7.50-7.33 (m, 3H), 7.24(d, J = 2.9 Hz, 1H), 7.06 (dd, J = 9.0, 3.0 Hz, 1H), 6.80 (d, J = 8.7Hz, 1H), 3.81 (s, 3H). 280 N-(3-carbamoylphenyl)-2-(4- ESI-MS m/z calc.¹H NMR (400 MHz, DMSO-d6) δ methoxy-2-methylphenoxy)- 444.13, found445.4 10.60 (s, 1H), 8.26-8.14 (m, 1H), 5-(trifluoromethyl)benzamide(M + 1)+; Retention 7.97 (d, J = 2.4 Hz, 2H), time (Method B): 7.93-7.81(m, 1H), 7.76 (dd, J = 8.9, 2.4 Hz, 1.82 minutes (3 1H), 7.66-7.57 (m,1H), minute run). 7.48-7.30 (m, 2H), 7.13 (d, J = 8.8 Hz, 1H), 6.94 (d,J = 3.0 Hz, 1H), 6.87 (dd, J = 8.8, 3.0 Hz, 1H), 6.74 (d, J = 8.8 Hz,1H), 3.76 (s, 3H), 2.11 (s, 3H). 281 N-(3-carbamoylphenyl)-2- ESI-MS m/zcalc. ¹H NMR (400 MHz, DMSO-d6) δ (2,4-dimethoxyphenoxy)-5- 460.12,found 461.2 10.50 (s, 1H), 8.21-8.14 (m, 1H), (trifluoromethyl)benzamide(M + 1)+; Retention 8.02-7.92 (m, 2H), time (Method B): 7.92-7.83 (m,1H), 7.75 (dd, J = 8.9, 2.4 Hz, 1.79 minutes (3 1H), 7.66-7.56 (m, 1H),minute run). 7.48-7.32 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 6.81-6.70 (m,2H), 6.62 (dd, J = 8.7, 2.8 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H). 282N-(3-carbamoylphenyl)-2-(2- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δisopropoxyphenoxy)-5- 458.15, found 459.4 10.45 (s, 1H), 8.25-8.11 (m,1H), (trifluoromethyl)benzamide (M + 1)+; Retention 8.04-7.92 (m, 2H),time (Method B): 7.92-7.83 (m, 1H), 7.78 (dd, J = 8.8, 2.4 Hz, 1.88minutes (3 1H), 7.67-7.55 (m, 1H), minute run). 7.48-7.31 (m, 3H),7.31-7.16 (m, 2H), 7.13-6.99 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H),4.65-4.48 (m, 1H), 1.07 (d, J = 6.0 Hz, 6H). 283N-(3-carbamoylphenyl)-2-(2- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δchlorophenoxy)-5- 434.06, found 435.3 10.63 (s, 1H), 8.20-8.14 (m, 1H),(trifluoromethyl)benzamide (M + 1)+; Retention 8.03 (d, J = 2.3 Hz, 1H),7.96 (s, time (Method B): 1H), 7.91-7.78 (m, 2H), 1.76 minutes (37.68-7.56 (m, 2H), 7.54-7.24 (m, 5H), minute run). 6.91 (d, J = 8.7 Hz,1H). 284 N-(3-carbamoylphenyl)-2-(4- ESI-MS m/z calc. ¹H NMR (400 MHz,DMSO-d6) δ chloro-2-methylphenoxy)-5- 448.08, found 449.3 10.63 (s, 1H),8.22-8.13 (m, 1H), (trifluoromethyl)benzamide (M + 1)+; Retention 8.00(d, J = 2.3 Hz, 1H), 7.96 (s, time (Method B): 1H), 7.86-7.73 (m, 2H),1.92 minutes (3 7.64-7.53 (m, 1H), 7.50-7.29 (m, 4H), minute run). 7.15(d, J = 8.7 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 2.16 (s, 3H). 285N-(3-carbamoylphenyl)-2-(2- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO-d6) δ(difluoromethoxy)phenoxy)- 466.10, found 467.4 10.60 (s, 1H), 8.21-8.12(m, 1H), 5-(trifluoromethyl)benzamide (M + 1)+; Retention 8.02 (d, J =2.3 Hz, 1H), 7.96 (s, time (Method B): 1H), 7.83 (dd, J = 8.6, 2.2 Hz,2H), 1.77 minutes (3 7.63-7.56 (m, 1H), minute run). 7.47-6.89 (m, 8H).286 N-(3-carbamoylphenyl)-2-(4- ESI-MS m/z calc. ¹H NMR (400 MHz,DMSO-d6) δ chloro-2-methoxyphenoxy)- 464.08, found 465.3 10.55 (s, 1H),8.24-8.12 (m, 1H), 5-(trifluoromethyl)benzamide (M + 1)+; Retention8.05-7.93 (m, 2H), 7.86 (dd, J = 7.7, time (Method B): 2.1 Hz, 1H), 7.76(dd, J = 8.8, 1.84 minutes (3 2.3 Hz, 1H), 7.64-7.55 (m, 1H), minuterun). 7.47-7.35 (m, 2H), 7.36-7.29 (m, 2H), 7.11 (dd, J = 8.5, 2.4 Hz,1H), 6.84 (d, J = 8.8 Hz, 1H), 3.77 (s, 3H). 287N-(3-carbamoylphenyl)-2-(2- ESI-MS m/z calc. 1H NMR (400 MHz, DMSO-d6) δmethoxyphenoxy)-5- 430.11, found 431.5 10.53 (s, 1H), 8.22-8.14 (m, 1H),(trifluoromethyl)benzamide (M + 1)+; Retention 8.01-7.94 (m, 2H), time(Method B): 7.94-7.82 (m, 1H), 7.77 (dd, J = 8.9, 2.4 Hz, 1.78 minutes(3 1H), 7.64-7.56 (m, 1H), minute run). 7.47-7.35 (m, 2H), 7.35-7.27 (m,2H), 7.27-7.18 (m, 1H), 7.12-7.00 (m, 1H), 6.78 (d, J = 8.8 Hz, 1H),3.75 (s, 3H). 288 N-(3-carbamoylphenyl)-2-(4- ESI-MS m/z calc. ¹H NMR(400 MHz, DMSO) δ fluoro-2-methoxyphenoxy)-5- 448.10, found 449.5 10.54(s, 1H), 8.18 (s, 1H), (trifluoromethyl)benzamide (M + 1)+; Retention7.97 (d, J = 2.3 Hz, 2H), 7.88 (d, J = 8.1 Hz, time (Method B): 1H),7.77 (dd, J = 8.8, 2.3 Hz, 1.47 minutes (3 1H), 7.61 (d, J = 7.8 Hz,1H), minute run). 7.48-7.34 (m, 3H), 7.18 (dd, J = 10.7, 2.9 Hz, 1H),6.92-6.85 (m, 1H), 6.80 (d, J = 8.7 Hz, 1H), 3.76 (s, 3H). 289N-(3-carbamoylphenyl)-2-(2- ESI-MS m/z calc. chloro-4-fluorophenoxy)-5-452.06, found 453.3 (trifluoromethyl)benzamide (M + 1)+; Retention time(Method B): 1.83 minutes (3 minute run). 290 N-(3-carbamoylphenyl)-2-(4-ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO) δ fluoro-2-methoxyphenoxy)-5-448.10, found 449.2 10.52 (s, 1H), 8.17 (s, 1H),(trifluoromethyl)benzamide (M + 1)+; Retention 7.98 (m, 2H), 7.86 (m,1H), 7.79 (dd, J = 8.8, time (Method B): 2.3 Hz, 1H), 7.60 (d, J = 7.8Hz, 1.69 minutes (3 1H), 7.43 (t, J = 7.9 Hz, 1H), minute run). 7.38 (s,1H), 7.25 (m, 2H), 7.15 (m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 3.73 (s, 3H).

Example 218N-(3-carbamoyl-2-methylphenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide(291)

Step 1: 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzaldehyde

To a solution of 2-fluoro-5-(trifluoromethyl)benzaldehyde (11.6 mL, 82.1mmol) and 4-fluoro-2-methyl-phenol (11.4 g, 90.3 mmol) in DMF (80 mL)was added cesium carbonate (29.4 g, 90.3 mmol), and the mixture washeated at 100° C. for 1.5 hours. The reaction was cooled to roomtemperature and filtered, washing with ethyl acetate. The solvent wasconcentrated under reduced pressure. The residue was partitioned betweenethyl acetate (200 mL) and water (100 mL). The two layers wereseparated, and the aqueous layer was extracted with ethyl acetate (2×100mL). The organic layers were combined, dried over sodium sulfate, andfiltered, and the solvent was evaporated under reduced pressure to givea brown liquid. The crude product was purified on 330 g of silica gelutilizing a gradient of 0-15% ethyl acetate in hexane to yield2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzaldehyde (16.4 g,67%) as a yellow solid. ESI-MS m/z calc. 298.06, found 299.3 (M+1)+;Retention time (Method B): 2.22 minutes (3 min run). ¹H NMR (400 MHz,DMSO) δ 10.53 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.94 (dd, J=8.8, 2.4 Hz,1H), 7.32 (dd, J=9.3, 3.1 Hz, 1H), 7.30-7.25 (m, 1H), 7.22-7.14 (m, 1H),6.84 (d, J=8.8 Hz, 1H), 2.18 (s, 3H) ppm.

Step 2: 2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoic Acid

To a solution of2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzaldehyde (16.4 g,55.0 mmol) in tBuOH (164 mL), water (103 mL) and acetonitrile (103 mL)was added sodium dihydrogen phosphate (10.6 g, 5.5 mL, 88.0 mmol),2-methyl-2-butene (19.3 g, 29.1 mL, 275.1 mmol) and NaClO₂ (14.9 g,165.1 mmol). The reaction mixture was stirred at 25° C. for 2 hours. Themixture was acidified with aqueous 1N HCl and was diluted with ethylacetate (200 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×100 mL). The organic layers werecombined, dried with sodium sulfate, filtered and evaporated to give apale yellow sticky solid that was tritrated with hexanes, then filteredto give 2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoic acid(16.5 g, 95%) as a white solid. ESI-MS m/z calc. 314.06, found 315.2(M+1)+; Retention time (Method B): 1.96 minutes (3 min run). ¹H NMR (400MHz, DMSO) δ 12.17 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.83 (dd, J=8.8, 2.2Hz, 1H), 7.27 (dd, J=9.3, 3.0 Hz, 1H), 7.20-6.99 (m, 2H), 6.84 (d, J=8.7Hz, 1H), 2.14 (s, 3H) ppm.

Step 3:N-(3-carbamoyl-2-methylphenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide(291)

To a reaction vial loaded with 3-amino-2-methylbenzamide (15.0 mg, 0.10mmol), 2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoic acid (63mg, 0.20 mmol), HATU (38 mg, 0.10 mmol) and NMP (1 mL) was addedtriethylamine (30 mg, 0.30 mmol), and the reaction was heated at 80° C.for 18 hours. The reaction mixture was filtered and purified by reversephase HPLC (gradient of 10-99% acetonitrile in water containing HCl as amodifier) to obtainN-(3-carbamoyl-2-methylphenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamideacid (9.5 mg, 21%) as a white solid. ESI-MS m/z calc. 446.13, found447.4 (M+1)+; Retention time (Method B): 1.95 minutes (3 min run). ¹HNMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.80(dd, J=8.8, 2.4 Hz, 1H), 7.76 (s, 1H), 7.70-7.56 (m, 1H), 7.41 (s, 1H),7.34-7.06 (m, 5H), 6.83 (d, J=8.8 Hz, 1H), 2.23 (s, 3H), 2.18 (s, 3H)ppm.

The compounds set forth in Table 18 were prepared by methods analogousto the preparation of compound 291.

TABLE 18 Additional Compounds Prepared By Methods Analogous to Example218 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 292N-(3-carbamoyl-4- ESI-MS m/z calc. methoxyphenyl)-2-(4-fluoro- 462.12,found 467.3 2-methylphenoxy)-5- (M + 1)+; Retention(trifluoromethyl)benzamide time (Method B): 1.98 minutes (3 minute run).293 N-(3-carbamoyl-4- ESI-MS m/z calc. chlorophenyl)-2-(4-fluoro-2-462.12, found 463.3 methylphenoxy)-5- (M + 1)+; Retention(trifluoromethyl)benzamide time (Method B): 2.01 minutes (3 minute run).294 N-(3-carbamoyl-4- ESI-MS m/z calc. methylphenyl)-2-(4-fluoro-2-446.13, found 447.1 methylphenoxy)-5- (M + 1)+; Retention(trifluoromethyl)benzamide time (Method B): 1.98 minutes (3 minute run).296 N-(3-carbamoylphenyl)-2-(4- ESI-MS m/z calc. ¹H NMR (400 MHz, DMSO)δ fluoro-2-methylphenoxy)-5- 432.11 found 433.3 10.62 (s, 1H), 8.18 (s,1H), (trifluoromethyl)benzamide (M + 1)+; Retention 7.98 (m, 2H), 7.85(d, J = 8.2 Hz, 1H), time (Method B): 7.78 (dd, J = 8.8, 2.1 Hz, 1H),1.88 minutes (3 7.60 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 16.8, minuterun). 8.9 Hz, 2H), 7.23 (m, 2H), 7.14 (td, J = 8.6, 3.1 Hz, 1H), 6.82(d, J = 8.7 Hz, 1H), 2.15 (s, 3H). 297 N-(4-carbamoylphenyl)-2-(2-ESI-MS m/z calc. chloro-4-fluoro-phenoxy)-6- 432.11 found 433.3(trifluoromethyl)benzamide (M + 1)+; Retention time (Method B): 1.66minutes (3 minute run).

Example 219N-(3-Carbamoylphenyl)-2-[4-fluoro-2-(methoxy)phenoxy]-4-(trifluoromethyl)benzamide(298)

Step 1: N-(3-carbamoylphenyl)-2-fluoro-4-(trifluoromethyl)benzamide

To 3-aminobenzamide (1.20 g, 8.83 mmol) in dichloromethane (20 mL),N,N-dimethylformamide (6 mL), and pyridine (6.98 g, 7.14 mL, 88.3 mmol)at 0° C. was added a solution of 2-fluoro-5-(trifluoromethyl)benzoylchloride (2.00 g, 8.83 mmol) in dichloromethane (4 mL) drop wise. Theresulting precipitate was filtered and washed with minimaldichloromethane. The solid was re-suspended in water, filtered, anddried under vacuum to provideN-(3-carbamoylphenyl)-2-fluoro-4-(trifluoromethyl)benzamide (2.02 g,70%) as a white solid. ESI-MS m/z calc. 326.07, found 327.3 (M+1)⁺;retention time (Method B): 1.25 minutes (3 minute run). ¹H NMR (400 MHz,DMSO-d6) δ 10.75 (s, 1H), 8.19 (t, J=1.8 Hz, 1H), 7.99 (s, 1H),7.96-7.88 (m, 2H), 7.85 (ddd, J=8.2, 2.1, 1.0 Hz, 1H), 7.75 (d, J=8.2Hz, 1H), 7.67-7.59 (m, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.39 (s, 1H).

Step 2:N-(3-Carbamoylphenyl)-2-[4-fluoro-2-(methoxy)phenoxy]-4-(trifluoromethyl)benzamide(298)

A mixture of N-(3-carbamoylphenyl)-2-fluoro-4-(trifluoromethyl)benzamide(50 mg, 0.15 mmol), 4-fluoro-2-methoxy-phenol (26 mg, 21 μL, 0.18 mmol))and potassium carbonate (64 mg, 0.46 mmol) was heated in DMF (0.5 mL) at100° C. for 1 hour. Filtration followed by HPLC purification (1-99%acetonitrile/5 mM HCl) affordedN-(3-carbamoylphenyl)-2-[4-fluoro-2-(methoxy)phenoxy]-4-(trifluoromethyl)benzamideas a white solid (41 mg, 59%). ESI-MS m/z calc. 448.10, found 449.3(M+1)+; Retention time (Method B): 1.57 minutes (3 minute run). ¹H NMR(400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.22-8.16 (m, 1H), 7.97 (br s, 1H),7.84 (d, J=7.9 Hz, 2H), 7.60 (dd, J=7.7, 1.3 Hz, 1H), 7.55 (d, J=7.2 Hz,1H), 7.42 (t, J=7.9 Hz, 1H), 7.38 (br s, 1H), 7.33 (dd, J=8.8, 5.8 Hz,1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.87 (td, J=8.6, 3.1 Hz, 1H), 6.84(s, 1H), 3.76 (s, 3H).

The compounds set forth in Table 19 were prepared by methods analogousto the preparation of compound 298.

TABLE 19 Additional Compounds Prepared By Methods Analogous to Example219 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 299N-(3-carbamoylphenyl)-2-[2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6)chloro-4-(methoxy)phenoxy]-4- calc. 464.08, δ 10.64 (s, 1H), 8.19 (t, J= 1.9 Hz, (trifluoromethyl)benzamide found 465.5 1H), 7.97 (s, 1H), 7.87(d, J = 7.9 Hz, (M + 1)+; 1H), 7.83 (dd, J = 7.9, 1.8 Hz, Retention time1H), 7.64-7.56 (m, 2H), (Method B): 7.42 (t, J = 7.9 Hz, 1H), 1.61minutes (3 7.39-7.33 (m, 2H), 7.22 (d, J = 3.0 Hz, minute run). 1H),7.04 (dd, J = 9.0, 3.0 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H), 3.80 (s, 3H).300 N-(3-carbamoylphenyl)-2-[4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6)fluorophenoxy]-4- calc. 418.09, δ 10.65 (s, 1H), 8.15 (t, J = 1.9 Hz,(trifluoromethyl)benzamide found 419.1 1H), 7.96 (s, 1H), 7.87 (d, J =8.4 Hz, (M + 1)+; 1H), 7.80 (ddd, J = 8.3, Retention time 2.2, 1.1 Hz,1H), 7.63 (dd, J = 8.1, (Method B): 1.6 Hz, 1H), 7.59 (dt, J = 7.9, 1.54minutes (3 1.3 Hz, 1H), 7.41 (t, J = 7.9 Hz, minute run). 1H), 7.37 (brs, 1H), 7.31-7.25 (m, 2H), 7.25-7.19 (m, 2H), 7.14 (d, J = 1.6 Hz, 1H).301 N-(3-carbamoylphenyl)-2-[2,4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6)(dimethoxy)phenoxy]-4- calc. 460.12, δ 10.54 (s, 1H), 8.20 (t, J = 1.9Hz, (trifluoromethyl)benzamide found 461.3 1H), 7.98 (br s, 1H), (M +1)+; 7.88-7.80 (m, 2H), 7.60 (dt, J = 7.8, Retention time 1.3 Hz, 1H),7.51 (dd, J = 8.2, 1.6 Hz, (Method B): 1H), 7.43 (t, J = 7.9 Hz, 1H),1.58 minutes (3 7.38 (br s, 1H), 7.25 (d, J = 8.8 Hz, minute run). 1H),6.78 (d, J = 2.6 Hz, 2H), 6.61 (dd, J = 8.8, 2.8 Hz, 1H), 3.80 (s, 3H),3.74 (s, 3H). 302 N-(3-carbamoylphenyl)-2-[4- ESI-MS m/z ¹H NMR (400MHz, DMSO-d6) chloro-2-(methoxy)phenoxy]-4- calc. 464.08, δ 10.58 (s,1H), 8.17 (t, J = 1.9 Hz, (trifluoromethyl)benzamide found 465.5 1H),7.97 (br s, 1H), (M + 1)+; 7.87-7.79 (m, 2H), 7.59 (t, J = 7.7 Hz,Retention time 2H), 7.42 (t, J = 7.9 Hz, 1H), (Method B): 7.37 (br s,1H), 7.29 (d, J = 2.4 Hz, 1.65 minutes (3 1H), 7.26 (d, J = 8.5 Hz, 1H),minute run). 7.09 (dd, J = 8.6, 2.4 Hz, 1H), 6.93 (s, 1H), 3.76 (s, 3H).

Example 2204-[[4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carbonyl]amino]-N,6-dimethyl-pyridine-2-carboxamide(265)

This compound was made in an analogous fashion to Example 71, exceptemploying 4-amino-N,6-dimethyl-pyridine-2-carboxamide in the amideformation step (Step 2). The yield of the desired product afterpurification was 5 mg (2%). ESI-MS m/z calc. 544.1182, found 545.0(M+1)+, 543.0 (M−1)−; retention time (Method C): 3.27 minutes (5 minuterun). ¹H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.95 (s, 1H), 8.60 (q,J=4.8 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.50 (d,J=8.8 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.13-7.04 (m, 2H), 3.78 (s, 3H),2.83 (d, J=4.9 Hz, 3H), 2.54 (s, 3H).

Example 221N-(3-carbamoyl-4-fluoro-phenyl)-6-(2-cyano-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzamide(295)

A mixture of6-bromo-N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-3-(trifluoromethyl)benzamide(60 mg, 0.14 mmol, prepared as described in Example 140), cesiumcarbonate (92 mg, 0.28 mmol) and 5-fluoro-2-hydroxy-benzonitrile (19.44mg, 0.1418 mmol) in toluene (0.6 mL) was bubbled with nitrogen. After2-3 minutes, copper iodide (15 mg, 0.07 mmol) was added, and thereaction mixture was stirred at 100° C. for 20 minutes. The reaction wasdiluted with ethyl acetate and water. The organic layer was concentratedin vacuo and purified by HPLC (10-99% acetonitrile/5 mM HCl) to provideN-(3-carbamoyl-4-fluoro-phenyl)-6-(2-cyano-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzamide(4 mg, 6%). ESI-MS m/z calc. 479.0705, found 480.1 (M+1)+; retentiontime (Method B): 1.61 minutes (3 minute run).

Example 2224-(6-((6-chloro-2-methoxypyridin-3-yl)oxy)-2-fluoro-3-(trifluoromethyl)benzamido)picolinamide(303)

To a suspension of6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (600 mg, 1.641 mmol, prepared as described in Example 128) and DMF(5 μL, 0.06457 mmol) in dichloromethane (9 mL) at 0° C. was added oxalylchloride (700 μL, 8.024 mmol) dropwise. The reaction was allowed to cometo room temperature and stirred for ˜30 min. The reaction mixture wasconcentrated, and the residue was taken up in dichloromethane andconcentrated (3×5 mL). A cold solution of the crude6-[(6-chloro-2-methoxy-3-pyridyl)oxy]-2-fluoro-3-(trifluoromethyl)benzoylchloride in dichloromethane (1 mL) was then added to5-aminopyridine-3-carboxamide (35 mg, 0.26 mmol) suspended indichloromethane (1 mL) and diisopropylethylamine (136 μL, 0.78 mmol) at0° C. The reaction was then allowed to warm to room temperature andstirred for 16 hours. The reaction was concentrated, dissolved in DMSOand purified by HPLC to afford4-(6-((6-chloro-2-methoxypyridin-3-yl)oxy)-2-fluoro-3-(trifluoromethyl)benzamido)picolinamide(1.5 mg, 2%). ESI-MS m/z calc. 484.79, found 485.0 (M+1)+; Retentiontime (Method B): 1.45 minutes (3 minutes run).

Example 223 E-VIPR Assay Method A for Detecting and Measuring NayInhibition Properties

Sodium ion channels are voltage-dependent proteins that can be activatedby inducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use, referred to asE-VIPR, are described in International Publication No. WO 2002/008748 A3and C.-J. Huang et al. Characterization of voltage-gated sodium channelblockers by electrical stimulation and fluorescence detection ofmembrane potential, 24 Nature Biotech. 439-46 (2006), both of which areincorporated by reference in their entirety. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, andparallel electrode pairs that are inserted into assay plate wells. Underintegrated computer control, this instrument passes user-programmedelectrical stimulus protocols to cells within the wells of themicrotiter plate.

16-20 hours prior to running the assay on E-VIPR, HEK cells expressing atruncated form of human NaV 1.8 with full channel activity were seededinto 384-well plates (Greiner #781091-1B), pre-coated with matrigel, ata density of 25,000 cells per well. 5% KIR2.1 Bacmam virus was added tothe final cell suspension before seeding into cell plates. HEK cellswere grown in DMEM media (exact composition is specific to each celltype and Nav subtype) supplemented with 10% FBS (Fetal Bovine Serum,qualified; Sigma #F4135), 1% NEAA (Non-Essential Amino Acids, Life Tech#11140), 1% HEPES (Life Tech #15630), 1% Pen-Strep(Penicillin-Streptomycin; Life Tech #15640) and 5 μg/ml Blasticidin(Gibco #R210-01). Cells were expanded in vented cap flasks, with 95%humidity and 5% CO₂.

Reagents and Stock Solutions:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

Compound Plates: Corning 384-well Polypropylene Round Bottom #3656

Cell Plates: 384-well tissue culture treated plates. Greiner #781091-1B

5% KIR 2.1 Bacmam virus (produced in-house), prepared as described inSection 3.3 of J. A. Fornwald et al., Gene Expression in Mammalian CellsUsing BacMam, a Modified Baculovirus System, 1350 Methods in MolecularBiology 95-116 (2016), the entire contents of which are incorporated byreference.

5 mM DiSBAC₆(3) (a voltage sensitive oxonol acceptor) (Aurora#00-100-010) in dry DMSO

5 mM CC2-DMPE (a membrane-bound coumarin phospholipid FRET donor)(Aurora #00-100-008) in dry DMSO

89 mM VABSC-1 in H₂O

Human Serum (HS, Millipore #S1P1-01KL, lot #2706671A)

Bath1 Buffer:

-   -   Sodium Chloride 160 mM (9.35 g/L), Potassium Chloride, 4.5 mM        (0.335 g/L), Glucose 10 mM (1.8 g/L), Magnesium Chloride        (Anhydrous) 1 mM (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L),        HEPES 10 mM (2.38 g/L) in water.

Na/TMA C1 Bath1 Buffer:

-   -   Sodium Chloride 96 mM (5.61 g/L), Potassium Chloride 4.5 mM        (0.335 g/L), Tetramethylammonium (TMA)-Cl 64 mM (7.01 g/L),        Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous) 1 mM        (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L) HEPES 10 mM (2.38        g/L) in water.

Hexyl Dye Solution (2×):

-   -   Bath1 Buffer containing 0.5% β-cyclodextrin (made fresh prior to        each use, Sigma #C4767), 8 μM CC2-DMPE and 2 μM DiSBAC₆(3). The        solution was made by adding 10% Pluronic F127 stock equal to        combined volumes of CC2-DMPE and DiSBAC₆(3). The order of        preparation was first mix Pluronic and CC2-DMPE, then add        DiSBAC₆(3), then while vortexing add Bath1/β-Cyclodextrin.

Compound Loading Buffer (2×): Na/TMA Cl Bath1 Buffer containing HS 50%(omitted in experiments run in the absence of HS), VABSC-1 1 mM, BSA0.2% (in Bath-1), KCl 9 mM, DMSO 0.75%.

Assay Protocol:

1) 400 nL of each compound was pre-spotted (in neat DMSO) intopolypropylene compound plates at 400× desired final concentration, in an11 point dose response, 3-fold dilution, resulting in a top dose of 3 μMfinal concentration in the cell plate. Vehicle control (neat DMSO), andpositive control (an established Nav1.8 inhibitor, 25 μM final in assayin DMSO) were added manually to the outermost columns of each platerespectively. The compound plate was backfilled with 80 ul per well ofCompound Loading Buffer resulting in a 400 fold dilution of compoundfollowing a 1:1 transfer of compound into the cell plate (Step 6). FinalDMSO concentration for all wells in the assay was 0.625% (0.75% DMSO wassupplemented to the Compound Loading Buffer for a final DMSOconcentration of 0.625%).

2) Hexyl Dye Solution was prepared.

3) Cell plates were prepared. On the day of the assay, the media wasaspirated, and the cells were washed three times with 80 μL of Bath-1buffer, maintaining 25 μL residual volume in each well.

4) 25 μL per well of Hexyl Dye Solution was dispensed into the cellplates. The cells were incubated for 20 minutes at room temp or ambientconditions in darkness.

5) 80 μL per well of Compound Loading Buffer was dispensed into compoundplates.

6) The cell plates were washed three times with 80 μL per well of Bath-1Buffer, leaving 25 μL of residual volume. Then 25 uL per well fromcompound plate was transferred to each cell plate. The mixture wasincubated for 30 minutes at room temp/ambient conditions.

7) The plate was read on E-VIPR using the current-controlled amplifierto deliver stimulation wave pulses using the following protocol: 1.25Amps, 2.5 ms pulse width biphasic waveform, 10 Hz for 10 seconds at ascan rate of 200 Hz. A pre-stimulus recording was performed for 0.5seconds to obtain the un-stimulated intensities baseline. Thestimulatory waveform was followed by 0.5 seconds of post-stimulationrecording to examine the relaxation to the resting state.

Data Analysis:

Data were analyzed and reported as normalized ratios of emissionintensities measured in the 460 nm and 580 nm channels. The response asa function of time was reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{( {intensity}_{460\mspace{14mu} {nm}} )}{( {intensity}_{580\mspace{14mu} {nm}} )}$

The data were further reduced by calculating the initial (R_(i)) andfinal (R_(f)) ratios. These were the average ratio values during part orall of the pre-stimulation period and during sample points during thestimulation period. The fluorescence ratio (R_(f)/R_(i)) was thencalculated and reported as a function of time.

Control responses were obtained by performing assays in the presence ofthe positive control, and in the absence of pharmacological agents (DMSOvehicle negative control). Responses to the negative (N) and positive(P) controls were calculated as above. The compound antagonist %activity A was then defined as:

$A = {\frac{X - N}{P - N} \times 100}$

where X is the ratio response of the test compound. Using this analysisMethod A protocol, dose response curves were plotted and IC₅₀ valueswere generated for various compounds of the present invention asreported below in Tables 20 and 20A.

E-VIPR Assay Method B for Detecting and Measuring Nay InhibitionProperties

Sodium ion channels are voltage-dependent proteins that can be activatedby inducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use, referred to asE-VIPR, are described in International Publication No. WO 2002/008748 A3and C.-J. Huang et al. Characterization of voltage-gated sodium channelblockers by electrical stimulation and fluorescence detection ofmembrane potential, 24 Nature Biotech. 439-46 (2006), both of which areincorporated by reference in their entirety. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, andparallel electrode pairs that are inserted into assay plate wells. Underintegrated computer control, this instrument passes user-programmedelectrical stimulus protocols to cells within the wells of themicrotiter plate.

16-20 hours prior to running the assay on E-VIPR, HEK cells expressing atruncated form of human Nay 1.8 with full channel activity were seededinto 384-well plates (Greiner #781091-1B), pre-coated with matrigel, ata density of 25,000 cells per well. 5% KIR2.1 Bacmam virus was added tothe final cell suspension before seeding into cell plates. HEK cellswere grown in DMEM media (exact composition is specific to each celltype and Nav subtype) supplemented with 10% FBS (Fetal Bovine Serum,qualified; Sigma #F4135), 1% NEAA (Non-Essential Amino Acids, Life Tech#11140), 1% HEPES (Life Tech #15630), 1% Pen-Strep(Penicillin-Streptomycin; Life Tech #15640) and 5 μg/ml Blasticidin(Gibco #R210-01). Cells were expanded in vented cap flasks, with 95%humidity and 5% CO₂.

Reagents and Stock Solutions:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

Compound Plates: Corning 384-well Polypropylene Round Bottom #3656

Cell Plates: 384-well tissue culture treated plates. Greiner #781091-1B

5% KIR 2.1 Bacmam virus (produced in-house), prepared as described inSection 3.3 of J. A. Fornwald et al., Gene Expression in Mammalian CellsUsing BacMam, a Modified Baculovirus System, 1350 Methods in MolecularBiology 95-116 (2016), the entire contents of which are incorporated byreference.

5 mM DiSBAC₆(3) (a voltage sensitive oxonol acceptor) (Aurora#00-100-010) in dry DMSO

5 mM CC2-DMPE (a membrane-bound coumarin phospholipid FRET donor)(Aurora #00-100-008) in dry DMSO

89 mM VABSC-1 in H₂O. VABSC-1 (Aurora #00-100-390, Voltage AssayBackground Suppression Compound) suppress background signal to provideoptimal assay performance

Human Serum (HS, Millipore #S1P1-01KL, lot #2706671A)

Bath1 Buffer:

-   -   Sodium Chloride 160 mM (9.35 g/L), Potassium Chloride, 4.5 mM        (0.335 g/L), Glucose 10 mM (1.8 g/L), Magnesium Chloride        (Anhydrous) 1 mM (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L),        HEPES 10 mM (2.38 g/L) in water.

Na/TMA C1 Bath1 Buffer:

-   -   Sodium Chloride 96 mM (5.61 g/L), Potassium Chloride 4.5 mM        (0.335 g/L), Tetramethylammonium (TMA)-Cl 64 mM (7.01 g/L),        Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous) 1 mM        (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L) HEPES 10 mM (2.38        g/L) in water.

Hexyl Dye Solution (2×):

-   -   Bath1 Buffer containing 0.5% β-cyclodextrin (made fresh prior to        each use, Sigma #C4767), 8 μM CC2-DMPE and 2 μM DiSBAC₆(3). The        solution was made by adding 10% Pluronic F127 stock equal to        combined volumes of CC2-DMPE and DiSBAC₆(3). The order of        preparation was first mix Pluronic and CC2-DMPE, then add        DiSBAC₆(3), then while vortexing add Bath 1/J-Cyclodextrin.

Compound Loading Buffer (2×): Na/TMA Cl Bath1 Buffer, VABSC-1 1 mM, BSA0.2% (in Bath-1), KCl 9 mM, DMSO 0.75%.

Assay Protocol:

1) 400 nL of each compound was pre-spotted (in neat DMSO) intopolypropylene compound plates at 400× desired final concentration.Vehicle control (neat DMSO), and positive control (an established Nav1.8inhibitor, 25 μM final in assay in DMSO) were added to the outermostcolumns of each plate respectively. The compound plate was backfilledwith 80 uL per well of Compound Loading Buffer resulting in a 400 folddilution of compound following a 1:1 transfer of compound into the cellplate (Step 6). Final DMSO concentration for all wells in the assay was0.625% (0.75% DMSO was supplemented to the Compound Loading Buffer for afinal DMSO concentration of 0.625%).

2) Hexyl Dye Solution was prepared.

3) Cell plates were prepared. On the day of the assay, the media wasaspirated, and the cells were washed three times with 80 μL of Bath-1buffer, maintaining 25 μL residual volume in each well.

4) 25 μL per well of Hexyl Dye Solution was dispensed into the cellplates. The cells were incubated for 20 minutes at room temp or ambientconditions in darkness.

5) 80 μL per well of Compound Loading Buffer was dispensed into compoundplates.

6) The cell plates were washed three times with 80 μL per well of Bath-1Buffer, leaving 25 μL of residual volume. Then 25 uL per well fromcompound plate was transferred to each cell plate. The mixture wasincubated for 30 minutes at room temp/ambient conditions.

7) The plate was read on E-VIPR using the current-controlled amplifierto deliver stimulation wave pulses using the following protocol: 1.25Amps, 2.5 ms pulse width biphasic waveform, 10 Hz for 10 seconds at ascan rate of 200 Hz. A pre-stimulus recording was performed for 0.5seconds to obtain the un-stimulated intensities baseline. Thestimulatory waveform was followed by 0.5 seconds of post-stimulationrecording to examine the relaxation to the resting state.

Data Analysis:

Data were analyzed and reported as normalized ratios of emissionintensities measured in the 460 nm and 580 nm channels. The response asa function of time was reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{( {intensity}_{460\mspace{14mu} {nm}} )}{( {intensity}_{580\mspace{14mu} {nm}} )}$

The data were further reduced by calculating the initial (R_(i)) andfinal (R_(f)) ratios. These were the average ratio values during part orall of the pre-stimulation period and during sample points during thestimulation period. The fluorescence ratio (R_(f)/R_(i)) was thencalculated and reported as a function of time.

Control responses were obtained by performing assays in the presence ofthe positive control, and in the absence of pharmacological agents (DMSOvehicle negative control). Responses to the negative (N) and positive(P) controls were calculated as above. The compound antagonist %activity A was then defined as:

$A = {\frac{X - N}{P - N} \times 100}$

where X is the ratio response of the test compound. Using this analysisMethod B protocol, dose response curves were plotted and IC₅₀ valueswere generated for various compounds of the present invention asreported below in Table 20B.

Results:

The IC₅₀ values determined for the compounds of the invention arereported in Tables 20, 20A, and 20B.

TABLE 20 IC₅₀ Values of Compounds 1-26 of the Invention in E-VIPR AssayMethod A Nav1.8 MedChem Optical Assay EVIPR Assay Method Compound NumberA HS IC₅₀ (uM) 1 0.0007 2 0.001 3 0.001 4 0.002 5 0.002 6 0.003 7 0.0038 0.003 9 0.003 10 0.003 11 0.004 12 0.004 13 0.004 14 0.006 15 0.007 160.007 17 0.008 18 0.009 19 0.01 20 0.01 21 0.01 22 0.011 23 0.014 240.018 25 0.018 26 0.002

TABLE 20A IC₅₀ Values of Compounds 27-246, 264, 265, 295, and 303 of theInvention in E-VIPR Assay Method A Nav1.8 MedChem Optical Assay EVIPRAssay Method Compound Number A HS IC₅₀ (uM) 27 0.087 28 0.108 29 0.11230 0.02 31 0.155 32 0.055 33 0.52 34 0.083 35 0.25 36 0.215 37 0.89 380.7 39 0.21 40 0.034 41 0.56 42 0.4 43 0.04 44 0.005 45 0.001 46 1.2 470.022 48 0.023 49 0.13 50 0.051 51 0.009 52 0.014 53 0.017 54 0.007 550.018 56 0.26 57 0.017 58 0.19 59 0.007 60 0.185 61 0.038 62 0.011 630.14 64 0.185 65 0.079 66 0.038 67 0.042 68 0.021 69 0.056 70 0.053 710.04 72 0.175 73 0.023 74 0.022 75 0.026 76 0.35 77 0.15 78 0.097 790.069 80 0.127 81 0.038 82 0.092 83 0.048 84 0.58 85 0.32 86 0.032 870.15 88 0.049 89 0.044 90 0.038 91 0.04 92 0.002 93 0.063 94 0.018 950.045 96 0.054 97 0.02 98 0.015 99 0.003 100 0.009 101 0.135 102 0.022103 0.034 104 0.064 105 0.044 106 0.015 107 0.123 108 0.05 109 0.065 1100.055 111 0.2 112 0.043 113 0.084 114 0.017 115 0.006 116 0.145 117 0.18118 0.1 119 0.048 120 0.005 121 0.18 122 0.056 123 0.005 124 0.22 1250.034 126 0.047 127 0.004 128 0.018 129 0.069 130 0.027 131 0.17 1320.14 133 0.43 134 0.068 135 0.14 136 0.14 137 0.005 138 1.4 139 0.085140 0.005 141 0.103 142 0.31 143 0.01 144 0.023 145 0.009 146 0.039 1470.13 148 0.85 149 1.5 150 0.29 151 0.52 152 0.017 153 0.022 154 0.055155 0.017 156 0.56 157 1 158 0.15 159 1.7 160 0.41 161 0.15 162 0.17 1630.011 164 1.6 165 0.34 166 0.005 167 0.045 168 0.14 169 0.113 170 0.014171 0.035 172 0.012 173 0.052 174 0.088 175 0.038 176 0.19 177 0.46 1780.076 179 0.01 180 0.075 181 2.1 182 0.41 183 0.099 184 0.5 185 0.066186 0.19 187 0.053 188 0.16 189 0.006 190 0.032 191 0.12 192 0.42 1930.016 194 0.021 195 0.011 196 0.044 197 0.46 198 0.15 199 0.17 200 >3.1201 0.001 202 0.04 203 0.046 204 0.6 205 0.15 206 0.045 207 0.027 2080.013 209 0.05 210 0.14 211 0.006 212 0.054 213 0.009 214 0.66 215 0.018216 0.008 217 1.1 218 0.002 219 0.0009 220 0.005 221 0.014 222 0.003 2230.008 224 0.009 225 0.003 226 0.01 227 0.002 228 0.007 229 0.047 2300.25 231 0.009 232 0.017 233 0.004 234 0.004 235 0.005 236 0.045 2370.012 238 0.400 239 2.7 240 0.011 241 0.038 242 0.044 243 0.024 2440.073 245 0.036 246 0.021 264 0.054 265 1.45 295 0.2 303 0.19

TABLE 20B IC₅₀ Values of Compounds 247-263, 266-294, and 296-302 of theInvention in E-VIPR Assay Method B Nav1.8 MedChem Optical Assay EVIPRAssay Method B Compound Number HS IC₅₀ (uM) 247 0.033 248 0.011 249 0.06250 0.065 251 0.091 252 0.036 253 0.88 254 0.26 255 7.2 256 0.55 2570.415 258 0.085 259 0.065 260 0.166 261 1.2 262 >25 263 >25 266 17 2670.007 268 0.014 269 0.009 270 0.009 271 0.02 272 0.008 273 0.03 2740.002 275 0.165 276 0.098 277 0.25 278 0.021 279 0.056 280 0.042 2810.039 282 0.13 283 0.082 284 0.043 285 0.072 286 0.02 287 0.084 2880.034 289 0.036 290 0.1 291 1.4 292 0.27 293 0.033 294 0.037 296 0.018297 0.04 298 0.014 299 0.13 300 0.061 301 0.057 302 0.026

The IC₅₀ values for the compounds described previously in U.S. Pat. No.8,779,197 were also determined by Method A and are reported in Table 21.The compound numbers C1-C8 and C11 referenced in Table 21 refer to thecorresponding compounds 1-8 and 11 in U.S. Pat. No. 8,779,197. Asevidenced by a comparison of the data in Tables 20, 20A, and 20B withthe data in Table 21, the compounds of the invention are more potentthan the compounds described in U.S. Pat. No. 8,779,197.

TABLE 21 Comparative IC₅₀ Values of Compounds Described in U.S. Pat. No.8,779,197 in E-VIPR Assay Method A. Compound Number IC₅₀ (μM) C1 >3.1C2 >3.1 C3 >3.1 C4 >3.1 C5 >3.1 C6 >3.1 C7 2.8 C8 0.985  C11 2.65

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

1. (canceled)
 2. A compound of formula (I-A)

or a pharmaceutically acceptable salt thereof, wherein: L is O, C(R)₂,or a single bond; X₅ is N or CR₅; X₆ is N or CR₆; X₇ is N or CR₇; X₉ isN or CR₉; X₁₀ is N or CR₁₀; X₁₁ is N or CR₁₁; each R is independently Hor C₁-C₆ alkyl; R_(2a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R_(3a) is H, halo, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R_(4a) is H, halo,OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₅,R₆, and R₇ are defined as follows: (i) R₅, R₆, and R₇ are eachindependently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w); (ii)R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylamino, or —W—(CH₂)_(n)—R_(w); and R₆ and R₇,together with the carbon atoms to which they are attached, forma ring offormula:

or (iii) R₅ and R₆, together with the carbon atoms to which they areattached, form a ring of formula:

and R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w): R₈ is H or —O—(CH₂)_(n)—R_(w);R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w); or R₁₂and R₁₃, together with the carbon atoms to which they are attached, forma ring of formula:

Y₁, Y₂, Z₁, and Z₂ are each independently O or C(R₁₄)₂; each R₁₄ isindependently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl; each W isindependently O or a single bond; each R_(w) is independently 3-6membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; and n is 0or 1; wherein when R₈ is H, then at least one of X₅, X₆, and X₇ is not Nor CH; wherein when X₇ is CR₇ and R₇ is C₁-C₆ alkyl, then R_(2a) is notH; wherein when R_(4a) is halo, then R_(2a) is not H; wherein no morethan one of X₅, X₆, and X₇ is N; wherein no more than one of X₉, X₁₀,and X₁₁ is N. 3-16. (canceled)
 17. The compound of claim 2, wherein thecompound is selected from the group of compounds identified in Tables 1,1A, and 1B, or a pharmaceutically acceptable salt thereof.
 18. Thecompound of claim
 2. 19. (canceled)
 20. A pharmaceutical compositioncomprising the compound of claim 2, or a pharmaceutically acceptablesalt thereof, and one or more pharmaceutically acceptable carriers orvehicles.
 21. A method of inhibiting a voltage-gated sodium channel in asubject comprising administering to the subject the compound of claim 2,or a pharmaceutically acceptable salt thereof.
 22. (canceled)
 23. Amethod of treating or lessening the severity in a subject of chronicpain, gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, postsurgical pain,visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome,incontinence, pathological cough, or cardiac arrhythmia comprisingadministering to the subject an effective amount of the compound ofclaim 2, or a pharmaceutically acceptable salt thereof. 24-34.(canceled)
 35. The method of claim 23, wherein said subject is treatedwith one or more additional therapeutic agents administered concurrentlywith, prior to, or subsequent to treatment with the compound orpharmaceutically acceptable salt.
 36. A compound of formula (I-B)

or a pharmaceutically acceptable salt thereof, wherein: L is O, C(R)₂,or a single bond; X_(1a) is N or CH; X_(2a) is N, N⁺—O⁻, or CR_(2a);X_(3a) is N or CR_(3a); X_(4a) is N or CR_(4a); X₅ is N or CR₅; X₆ is Nor CR₆; X₇ is N or CR₇; X₉ is N or CR₉; X₁₀ is N or CR₁₀; X₁₁ is N orCR₁₁; each R is independently H or C₁-C₆ alkyl; R_(2a) is H, halo, OH,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R_(3a)is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy; R_(4a) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; R₅, R₆, and R₇ are defined as follows: (i)R₅, R₆, and R₇ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w); (ii) R₅ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylamino, or—W—(CH₂)_(n)—R_(w); and R₆ and R₇, together with the carbon atoms towhich they are attached, forma ring of formula:

or (iii) R₅ and R₆, together with the carbon atoms to which they areattached, form a ring of formula:

and R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w): R₈ is H or —O—(CH₂)_(n)—R_(w);R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w); or R₁₂and R₁₃, together with the carbon atoms to which they are attached, forma ring of formula:

Y₁, Y₂, Z₁, and Z₂ are each independently O or C(R₁₄)₂; each R₁₄ isindependently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl; each W isindependently O or a single bond; each R_(w) is independently 3-6membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; and n is 0or 1; wherein when R₈ is H, then at least one of X₅, X₆, and X₇ is not Nor CH; wherein one or two of X_(1a), X_(2a), X_(3a), and X_(4a) is N orN⁺—O⁻; wherein no more than one of X₅, X₆, and X₇ is N; wherein no morethan one of X₉, X₁₀, and X₁₁ is N. 37-52. (canceled)
 53. The compound ofclaim 36, wherein the compound is selected from the group of compoundsidentified in Tables 1, 1A, and 1B, or a pharmaceutically acceptablesalt thereof.
 54. The compound of claim
 36. 55. (canceled)
 56. Apharmaceutical composition comprising the compound of claim 36, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers or vehicles.
 57. A method ofinhibiting a voltage-gated sodium channel in a subject comprisingadministering to the subject the compound of claim 36, or apharmaceutically acceptable salt thereof.
 58. (canceled)
 59. A method oftreating or lessening the severity in a subject of chronic pain, gutpain, neuropathic pain, musculoskeletal pain, acute pain, inflammatorypain, cancer pain, idiopathic pain, postsurgical pain, visceral pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence,pathological cough, or cardiac arrhythmia comprising administering tothe subject an effective amount of the compound of claim 36, or apharmaceutically acceptable salt thereof. 60-70. (canceled)
 71. Themethod of claim 59, wherein said subject is treated with one or moreadditional therapeutic agents administered concurrently with, prior to,or subsequent to treatment with the compound or pharmaceuticallyacceptable salt.
 72. A compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein: L is O, C(R)₂,or a single bond; X_(1b) is N or CR_(1b); X_(2b) is N or CR_(2b); X_(3b)is N or CR_(3b); X_(4b) is N or CR_(4b); X₅ is N or CR₅; X₆ is N or CR₆;X₇ is N or CR₇; X₉ is N or CR₉; X₁₀ is N or CR₁₀; X₁₁ is N or CR₁₁; eachR is independently H or C₁-C₆ alkyl; R_(1b) is H, halo, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R_(2b) is H, halo,OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R_(3b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R_(4b) is H, halo, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₅, R₆, and R₇ are defined asfollows: (i) R₅, R₆, and R₇ are each independently H, halo, CN, OH,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylamino, or —W—(CH₂)_(n)—R_(w); (ii) R₅ is H, halo, CN, OH, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylamino, or —W—(CH₂)_(n)—R_(w); and R₆ and R₇, together with thecarbon atoms to which they are attached, forma ring of formula:

or (iii) R₅ and R₆, together with the carbon atoms to which they areattached, form a ring of formula:

and R₇ is H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w): R₈ is H or —O—(CH₂)_(n)—R_(w);R₉, R₁₀, and R₁₁ are each independently H, halo, CN, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w);R₁₂ and R₁₃ are each independently H, halo, CN, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or —W—(CH₂)_(n)—R_(w); or R₁₂and R₁₃, together with the carbon atoms to which they are attached, forma ring of formula:

Y₁, Y₂, Z₁, and Z₂ are each independently O or C(R₁₄)₂; each R₁₄ isindependently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl; each W isindependently O or a single bond; each R_(w) is independently 3-6membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; and n is 0or 1; wherein when R₈ is H, then at least one of X₅, X₆, and X₇ is not Nor CH; wherein no more than two of X_(1b), X_(2b), X_(3b), and X_(4b) isN; wherein no more than one of X₅, X₆, and X₇ is N; wherein no more thanone of X₉, X₁₀, and X₁₁ is N. 73-87. (canceled)
 88. The compound ofclaim 72, wherein the compound is selected from the group of compoundsidentified in Tables 1, 1A, and 1B, or a pharmaceutically acceptablesalt thereof.
 89. The compound of claim
 72. 90. (canceled)
 91. Apharmaceutical composition comprising the compound of claim 72, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers or vehicles.
 92. A method ofinhibiting a voltage-gated sodium channel in a subject comprisingadministering to the subject the compound of claim 72, or apharmaceutically acceptable salt thereof.
 93. (canceled)
 94. A method oftreating or lessening the severity in a subject of chronic pain, gutpain, neuropathic pain, musculoskeletal pain, acute pain, inflammatorypain, cancer pain, idiopathic pain, postsurgical pain, visceral pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence,pathological cough, or cardiac arrhythmia comprising administering tothe subject an effective amount of the compound of claim 72, or apharmaceutically acceptable salt thereof. 95-105. (canceled)
 106. Themethod of claim 94, wherein said subject is treated with one or moreadditional therapeutic agents administered concurrently with, prior to,or subsequent to treatment with the compound or pharmaceuticallyacceptable salt.